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00:00:06,336 --> 00:00:09,072
WE ARE RIGHT ON TOP OF

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00:00:09,072 --> 00:00:09,673
THE HOUR.

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00:00:09,673 --> 00:00:12,609
SO LET'S GET STARTED.

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WELCOME ALL OF YOU ONLINE OR IN

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00:00:22,953 --> 00:00:23,620
PERSON.

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00:00:23,620 --> 00:00:27,424
THIS IS NCI GRAND ROUNDS AND IT

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IS ABSOLUTELY MY PLEASURE TO

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00:00:30,060 --> 00:00:36,800
BRUCE TODAY'S SPEAKER DR. TIM G

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RETEN, HE RECEIVED HADIS DEGREE

10
00:00:38,568 --> 00:00:40,871
FROM THE UNIVERSITY OF GERMANY,

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HE COMPLETED HIS RESIDENTIAL

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TRAINING IN INTERNAL MEDICINE

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ALONG WITH HEMEATOLOGY,

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00:00:52,949 --> 00:00:53,750
ONCOLOGY, HEPATOLOGY.

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00:00:53,750 --> 00:00:55,986
BEFORE MOVING TO NCI JOINED AS A

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TENURED TRACK INVESTIGATOR AND

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RIGHT NOW HE'S A CME DEPUTY

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INVESTIGATOR CHIEF FOR

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00:01:02,158 --> 00:01:03,627
[INDISCERNIBLE] MALIGNANT BRANCH

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00:01:03,627 --> 00:01:07,430
AND CO-DIRECTOR FOR THE NCI

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00:01:07,430 --> 00:01:08,465
LIVER CANCER PROGRAM.

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00:01:08,465 --> 00:01:10,533
TIM IS ACTUALLY TRULY A

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00:01:10,533 --> 00:01:11,601
PHYSICIAN SCIENTIST.

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00:01:11,601 --> 00:01:14,371
HIS EARLY WORK AND DOING POST

25
00:01:14,371 --> 00:01:17,407
DOC TRAINING AND JOHNS HOPKINS

26
00:01:17,407 --> 00:01:18,842
RELATED TO TUMOR IMMUNOLOGY, HE

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00:01:18,842 --> 00:01:19,743
USED THIS KNOWLEDGE TOGETHER

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00:01:19,743 --> 00:01:22,946
WITH HIS MEDICAL EXPERTISE IN

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00:01:22,946 --> 00:01:25,048
THE GASTRO, ONCOLOGY, AND

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00:01:25,048 --> 00:01:26,383
HEPATOLOGY, AND MEDICAL ONCOLOGY

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00:01:26,383 --> 00:01:28,385
FOR HIS RESEARCH DEVELOP NOVEL

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00:01:28,385 --> 00:01:30,086
TREATMENT FOR PATIENT WITH LIVER

33
00:01:30,086 --> 00:01:31,187
CANCER.

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00:01:31,187 --> 00:01:34,557
HE HEADS THE RESEARCH TEAM TO

35
00:01:34,557 --> 00:01:35,725
STUDY THE MICROENVIRONMENT OF

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00:01:35,725 --> 00:01:39,930
CANCER IN THE [INDISCERNIBLE]

37
00:01:39,930 --> 00:01:46,036
MEL ANGIO  CARCINOMA.

38
00:01:46,036 --> 00:01:47,304
IN,A DITION HE HELPED CONDUCT

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00:01:47,304 --> 00:01:49,539
CLINICAL TRIAL FOR PATIENTS WITH

40
00:01:49,539 --> 00:01:51,274
GI CANCER, HE IS AMONG THE FIRST

41
00:01:51,274 --> 00:01:52,909
1 INVESTIGATE HOW THE IMMUNE

42
00:01:52,909 --> 00:01:55,845
CHECK POINT INHIBITOR WORKS IN

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00:01:55,845 --> 00:01:57,347
PATIENT WITH [INDISCERNIBLE]

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00:01:57,347 --> 00:02:00,183
WITH THE CONCEPT IN COMBINATION

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00:02:00,183 --> 00:02:03,954
TOGETHER WITH LOCAL REGIONAL

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00:02:03,954 --> 00:02:04,187
THERAPY.

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00:02:04,187 --> 00:02:08,124
WITHOUT READING HIS ACCOLADES,

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00:02:08,124 --> 00:02:11,761
MANY, MANY, MANY OF THOSE, I SAW

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00:02:11,761 --> 00:02:14,331
THE AWARD FROM NCI OUTSTANDING

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00:02:14,331 --> 00:02:16,800
MENTOR AWARD, THIS IS ACTUALLY

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00:02:16,800 --> 00:02:19,970
REALLY FANTASTIC, NIH DIRECTOR

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MERITS AWARD AND NIH DEPUTY

53
00:02:23,373 --> 00:02:25,175
DIRECTOR AWARD.

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00:02:25,175 --> 00:02:26,276
HE PUBLISHED MANY, MANY JOURNALS

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00:02:26,276 --> 00:02:28,712
IN THE FIELD AND HIS WORK IS

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00:02:28,712 --> 00:02:30,847
CONSIDERED TOP SIDED IN MANY,

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00:02:30,847 --> 00:02:34,851
MANY OF THOSE EMPLOY SOME OF

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00:02:34,851 --> 00:02:38,722
THOSE INCLUDE CCI, CONSIDERED AS

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00:02:38,722 --> 00:02:40,757
THE ADVANCE SCIENCE.

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PERSONALLY, I THINK IT'S

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EXTREMELY SMART AND VERY CLEVER

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TO WORK WITH MANY PEOPLES.

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SO WITHOUT FURTHER ADO, I WOULD

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00:02:48,732 --> 00:02:55,672
LIKE TO WELCOME TIM TO THE

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PODIUM.

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00:02:57,607 --> 00:02:58,975
[ APPLAUSE ]

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>> THANK YOU FOR THOSE
VERY,

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VERY KIND WORDS AND

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00:03:04,481 --> 00:03:05,015
INTRODUCTION.

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00:03:05,015 --> 00:03:07,550
SO THIS IS KIND OF THE MENU I

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00:03:07,550 --> 00:03:09,519
WILL TELL YOU, JUST TOUCH ON

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00:03:09,519 --> 00:03:11,054
HEALTHCARE DISPARITIES AND HOW

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00:03:11,054 --> 00:03:12,389
IT RELATES TO OUR PROJECTS AND

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00:03:12,389 --> 00:03:16,826
THEN I DECIDED TO BRIEFLY TELL

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00:03:16,826 --> 00:03:18,561
YOU ABOUT STUDIES THAT WE

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00:03:18,561 --> 00:03:22,665
FINISHED ONLY IN THE PAST 2 AND

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00:03:22,665 --> 00:03:24,434
HALF YEARS TOUCHING ON DIFFERENT

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00:03:24,434 --> 00:03:26,603
AREAS IN THE FIELD OF

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00:03:26,603 --> 00:03:28,104
IMMUNOTHERAPY OF LIVER CANCER,

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00:03:28,104 --> 00:03:30,273
LIVER DISEASE WE LOOK AT THE

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00:03:30,273 --> 00:03:31,474
SPECIFIC ENVIRONMENT, A LINGS

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00:03:31,474 --> 00:03:33,176
BIT OF THE MIKE ARE BIOME AND

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00:03:33,176 --> 00:03:37,447
HOW IT'S RELATED TO TREATMENT.

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00:03:37,447 --> 00:03:40,517
SO IF I START WITH THIS, THIS IS

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00:03:40,517 --> 00:03:41,718
OUR ESTIMATED DEATH RATES FOR

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00:03:41,718 --> 00:03:44,421
THE COMMON CAPSER IN THE UNITED

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00:03:44,421 --> 00:03:45,388
STATES AND [INDISCERNIBLE] FROM

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00:03:45,388 --> 00:03:48,224
THE GROUP LOOKED AT THIS AND SHE

89
00:03:48,224 --> 00:03:49,526
MADE THE OBSERVATION THAT LIVER

90
00:03:49,526 --> 00:03:52,095
CANCER IS THE ONLY CANCER WHERE

91
00:03:52,095 --> 00:03:54,097
NONHISPANIC WHITES HAVE THE

92
00:03:54,097 --> 00:03:57,734
LOWEST ANNUAL DEATH RATES IN

93
00:03:57,734 --> 00:04:03,540
COMPARE TO AFRICAN AMERICANS OR

94
00:04:03,540 --> 00:04:03,940
HISPANIC PATIENTS.

95
00:04:03,940 --> 00:04:05,341
INDICATING THERE IS A CLEAR

96
00:04:05,341 --> 00:04:06,309
DISPARITY IN THIS.

97
00:04:06,309 --> 00:04:07,677
WE ASKED, YOU KNOW WHY IS THIS,

98
00:04:07,677 --> 00:04:10,980
WHY WOULD THIS BE AND 1

99
00:04:10,980 --> 00:04:13,416
POTENTIAL REASON SYSTEM PROBABLY

100
00:04:13,416 --> 00:04:13,983
OBESITY.

101
00:04:13,983 --> 00:04:17,053
SO HAD IS THE PREVALENCE OF

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00:04:17,053 --> 00:04:18,688
OBESITY IN THE UNITED STATES

103
00:04:18,688 --> 00:04:19,789
AMONG NONHISPANIC WHITE ADULTS.

104
00:04:19,789 --> 00:04:22,992
IF YOU COMPARE THIS TO HISPANIC

105
00:04:22,992 --> 00:04:24,761
AND OBVIOUSLY THE DARKER YOU CAN

106
00:04:24,761 --> 00:04:26,062
SEE THE FREQUENCY IS, YOU CAN

107
00:04:26,062 --> 00:04:27,397
SEE HOW THIS SHOWS UP AND IF YOU

108
00:04:27,397 --> 00:04:29,332
GO TO THE BLACK ARK DULTS, YOU

109
00:04:29,332 --> 00:04:30,567
CAN SEE THERE ARE STATES WHERE

110
00:04:30,567 --> 00:04:38,608
MORE THAN 50% OF THE INDIVIDUALS

111
00:04:38,608 --> 00:04:39,776
DEMONSTRATE--ADULTS ARE OBESE.

112
00:04:39,776 --> 00:04:40,810
NOW OBVIOUSLY WE DON'T BELIEVE

113
00:04:40,810 --> 00:04:42,011
THAT OBESITY IS THE ONLY REASON

114
00:04:42,011 --> 00:04:44,447
ASK WE ARE CURRENTLY STUDYING

115
00:04:44,447 --> 00:04:48,284
DIFFERENT ENVIRONMENT FACTORS

116
00:04:48,284 --> 00:04:49,786
AND OTHERS POTENTIALLY

117
00:04:49,786 --> 00:04:50,587
IMMUNOLOGIC FACTORS THAT MAY

118
00:04:50,587 --> 00:04:51,254
EXPLAIN THIS.

119
00:04:51,254 --> 00:04:52,755
I THINK IT SETS THE STAGE A

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00:04:52,755 --> 00:04:56,392
LITTLE BIT YOU KNOW TO STUDY

121
00:04:56,392 --> 00:04:57,093
NONALCOHOLIC FATTY LIVER DISEASE

122
00:04:57,093 --> 00:04:58,895
AND THAT'S WHAT I WOULD LIKE TO

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00:04:58,895 --> 00:04:59,596
START WITH.

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00:04:59,596 --> 00:05:00,997
NOW THOSE WHO KNOW ME, KNOW THAT

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00:05:00,997 --> 00:05:06,636
WE USUALLY TRY TO ANY INTO

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00:05:06,636 --> 00:05:08,505
NICHES AND STUDY SOMETHING ELSE

127
00:05:08,505 --> 00:05:09,305
NOBODY ELSE STUDIED.

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00:05:09,305 --> 00:05:11,040
WHAT I WILL START WITH IS I WILL

129
00:05:11,040 --> 00:05:15,211
TELL YOU ABOUT A STUDY WE

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00:05:15,211 --> 00:05:16,045
COMPLETED, IT'S A PRECLINICAL

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00:05:16,045 --> 00:05:17,480
STUDY, A MOUSE STUDY WHERE WE

132
00:05:17,480 --> 00:05:19,249
LOOKED AT PLATELETS IN THE

133
00:05:19,249 --> 00:05:20,550
CONTEXT OF NONALCOHOLIC FATTY

134
00:05:20,550 --> 00:05:25,588
LIVER DEC AND HCC.

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00:05:25,588 --> 00:05:26,656
NOW FROM A CLINICAL PERSPECTIVE

136
00:05:26,656 --> 00:05:28,424
WE KNOW THAT PATIENTS WITH LIVER

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00:05:28,424 --> 00:05:30,793
DISEASE AND HEPATITIS B, THEY

138
00:05:30,793 --> 00:05:32,395
BENEFIT FROM ASPIRIN TREATMENT.

139
00:05:32,395 --> 00:05:35,265
YOU CAN SEE HERE, LARGE COHORT

140
00:05:35,265 --> 00:05:37,567
STUDY OUT OF SCANDINAVIAN

141
00:05:37,567 --> 00:05:41,104
CLEARLY REDUCES LIVER AND

142
00:05:41,104 --> 00:05:42,105
HCC RELATED MORTALITY.

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00:05:42,105 --> 00:05:44,507
SO THIS WOULD SUGGIEST AND WE

144
00:05:44,507 --> 00:05:46,142
KNOW THIS FROM ANY OTHER

145
00:05:46,142 --> 00:05:47,944
DISEASE, YOU KNOW THAT

146
00:05:47,944 --> 00:05:52,549
INHIBITING PLATE FUNCTION MAY BE

147
00:05:52,549 --> 00:05:53,449
A GOOD THING.

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00:05:53,449 --> 00:05:55,185
NOW WE TESTED THIS IN A MOUSE

149
00:05:55,185 --> 00:05:56,186
MODEL AND WE WILL SHOW YOU HOW

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00:05:56,186 --> 00:05:58,888
WE DID THIS, WE HAVE THE MOUSE

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00:05:58,888 --> 00:06:02,425
MODEL NOW HERE, WE CAN SCREEN

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00:06:02,425 --> 00:06:04,761
TUMORS SO WE INJECT TUMOR CELLS

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00:06:04,761 --> 00:06:07,697
AT 55.1 AND THEN WE PERFORM

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00:06:07,697 --> 00:06:09,032
SCANS AT DIFFERENT TIME POINTS

155
00:06:09,032 --> 00:06:12,569
AND YOU CAN SEE HERE ON THIS

156
00:06:12,569 --> 00:06:14,737
SLIDE, BASICALLY THE CT SCAN

157
00:06:14,737 --> 00:06:16,606
FROM THE MOUSE UNFORTUNATELY WE

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00:06:16,606 --> 00:06:23,012
PUT THE MOUSE WRONG WAY AROUND

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00:06:23,012 --> 00:06:25,315
IF WE COMPARE THIS TO THE HUMAN,

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00:06:25,315 --> 00:06:26,649
YOU SEE THE FRONT AND THE BACK,

161
00:06:26,649 --> 00:06:28,284
AND YOU CAN SEE THE TUMOR.

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00:06:28,284 --> 00:06:30,086
WE CAN SCAN THE MOUSE AND YOU

163
00:06:30,086 --> 00:06:30,920
CAN SEE BASICALLY FROM THE HEAD

164
00:06:30,920 --> 00:06:32,288
TO THE TAIL AND YOU WILL SEE

165
00:06:32,288 --> 00:06:35,825
FIRST THE LUNG AND THEN YOU WILL

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00:06:35,825 --> 00:06:37,026
SEE THE LIVER OF THIS MOUSE YOU

167
00:06:37,026 --> 00:06:39,395
SEE HERE AND YOU SEE HERE HOW

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00:06:39,395 --> 00:06:41,664
THE TUMOR IS ACTUALLY INSIDE THE

169
00:06:41,664 --> 00:06:43,399
LIVER AND OBVIOUSLY WE CAN

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MEASURE THIS IN AN EXPERIMENTAL

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00:06:45,235 --> 00:06:50,373
SETTING AND WE COMBINED THIS,

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NOW WITH ELIMINATION OF

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00:06:56,946 --> 00:06:58,948
PLATEMENTS USING AN ANTIBODY GP1

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00:06:58,948 --> 00:07:00,116
B, AND INTERESTING THING HERE,

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00:07:00,116 --> 00:07:02,685
IF THIS MOUSE IS FED A DIET TO

176
00:07:02,685 --> 00:07:04,153
INDUCE FATTY LIVER DISEASE, ALL

177
00:07:04,153 --> 00:07:06,923
OF A SUDDEN PLATELET INHIBITION

178
00:07:06,923 --> 00:07:11,327
HERE ACTUALLY CAUSES AN INCREASE

179
00:07:11,327 --> 00:07:12,695
OF TUMOR GROWTH.

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00:07:12,695 --> 00:07:13,930
THIS APPLIES TO SEVERAL MODELS,

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00:07:13,930 --> 00:07:17,100
THIS IS ANOTHER MODEL WHERE WE

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00:07:17,100 --> 00:07:17,767
INDUCE THROUGH DIET, LIVER

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00:07:17,767 --> 00:07:19,202
TUMORS AND AGAIN IN THIS CASE,

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00:07:19,202 --> 00:07:22,071
NOW, WE USE A PHARMAICOLOG

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00:07:22,071 --> 00:07:24,207
CALAWAY TO INHIBIT PLATEMENT

186
00:07:24,207 --> 00:07:27,810
FUNCTION AND YOU CAN SEE THAT

187
00:07:27,810 --> 00:07:29,679
INHIBITING PLATELET FUNCTION

188
00:07:29,679 --> 00:07:30,313
ACTUALLY PROGRESSING TUMORS AND

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00:07:30,313 --> 00:07:36,519
THIS IS NOT LIMITED TO HTC, WE

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00:07:36,519 --> 00:07:39,622
SEE THIS WITH 3 DIFFERENT LIVER

191
00:07:39,622 --> 00:07:40,890
METASTASIS MODELS AND WHEN WE

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00:07:40,890 --> 00:07:42,792
GROW THESE IN THE LIVERS, THEY

193
00:07:42,792 --> 00:07:43,593
ARE GROWING BIGGER.

194
00:07:43,593 --> 00:07:47,163
SO NOW YOU MAY SAY, WHAT'S GOING

195
00:07:47,163 --> 00:07:47,530
ON?

196
00:07:47,530 --> 00:07:49,432
FIRST I SHOWED YOU PLATELETS

197
00:07:49,432 --> 00:07:50,500
DECREASING INCIDENCE OF LIVER

198
00:07:50,500 --> 00:07:54,904
TUMORS, AND NOW IN OUR ANIMAL

199
00:07:54,904 --> 00:07:56,839
MODELS, I AM SHOWING YOU THE

200
00:07:56,839 --> 00:07:57,206
EXACT OPPOSITE.

201
00:07:57,206 --> 00:07:59,609
NOW I WANT TO MAKE SURE THAT I

202
00:07:59,609 --> 00:08:00,510
STRESS THAT ALL OUR STUDIES ARE

203
00:08:00,510 --> 00:08:02,578
DONE IN MICE THAT HAVE FATTY

204
00:08:02,578 --> 00:08:04,280
LIVER DISEASE, WE DON'T SEE THE

205
00:08:04,280 --> 00:08:05,214
ABSENCE OF FATTY LIVER DEC.

206
00:08:05,214 --> 00:08:08,151
SO WE LOOKED INTO THIS IN MORE

207
00:08:08,151 --> 00:08:09,686
DETAIL AND WE WENT AND STARTED

208
00:08:09,686 --> 00:08:11,888
READING AND 1 OF THE FACTORS

209
00:08:11,888 --> 00:08:14,357
THAT WE KNEW IS THAT PLATELETS

210
00:08:14,357 --> 00:08:15,625
ARE ACTIVATED IN INDIVIDUALS

211
00:08:15,625 --> 00:08:19,395
WITH FATTY LIVER DISEASE AND

212
00:08:19,395 --> 00:08:21,264
PLATELETS ARE ALSO A MAJOR

213
00:08:21,264 --> 00:08:23,800
SOURCE OF CD40 LIGAND, SO WE

214
00:08:23,800 --> 00:08:25,301
LOOKED AT CD40 LIGAND IN OUR

215
00:08:25,301 --> 00:08:26,336
MODEL AND INSIDE IF WE PUT MICE

216
00:08:26,336 --> 00:08:29,005
ON A DIET TO INDUCE FATTY LIVER

217
00:08:29,005 --> 00:08:30,540
DISEASE, CD40 IS INCREASED WITH

218
00:08:30,540 --> 00:08:31,708
DIFFERENT MODEL ANDS WE ALSO

219
00:08:31,708 --> 00:08:33,843
FIND THIS ACTUALLY IF WE TAKE

220
00:08:33,843 --> 00:08:35,511
BLOOD FROM PATIENTS WITH FATTY

221
00:08:35,511 --> 00:08:44,954
LIVER DISEASE, CD40 LIGAND IS

222
00:08:44,954 --> 00:08:47,123
INCREASE THE--WE CAN DO THE SAME

223
00:08:47,123 --> 00:08:49,459
THING, THIS DOES NOD APPLY TO A

224
00:08:49,459 --> 00:08:50,927
MOUSE THAT DOESN'T HAVE FATTY

225
00:08:50,927 --> 00:08:55,565
LIVER DISEASE AND IF WE DEPLETE

226
00:08:55,565 --> 00:08:57,300
CD40, THE [INDISCERNIBLE] MAY BE

227
00:08:57,300 --> 00:08:57,667
GONE.

228
00:08:57,667 --> 00:09:00,603
SAME THING HERE, NOW WE USE CD40

229
00:09:00,603 --> 00:09:02,038
LIGAND KNOCKOUT MICE, THERE'S NO

230
00:09:02,038 --> 00:09:04,540
CENTER FOR EXCELLENCE ON AGING

231
00:09:04,540 --> 00:09:07,276
ON THE VEHICLE, SO FAR, BUT IT'S

232
00:09:07,276 --> 00:09:08,811
REALLY THE CD40 THAT COMES FROM

233
00:09:08,811 --> 00:09:09,912
THE PLATELET THAT'S IMPORTANT

234
00:09:09,912 --> 00:09:13,783
AND WE DID THIS RATHER

235
00:09:13,783 --> 00:09:15,284
COMPLICATED EXPERIMENT WHERE WE

236
00:09:15,284 --> 00:09:19,822
ACTUALLY INJECT MICE THAT ARE

237
00:09:19,822 --> 00:09:22,392
PF4 DTR MICE, WHERE WE DEPLETE

238
00:09:22,392 --> 00:09:24,527
PLATELETS, WE PUT THEM ON THE

239
00:09:24,527 --> 00:09:26,729
MCD DIET SO THAT WE INDUCE SCEEZ

240
00:09:26,729 --> 00:09:29,699
AND INJECT LIVER TUMORS AND THEN

241
00:09:29,699 --> 00:09:31,567
WE TRANSFER CD40 LIGAND OR XOK

242
00:09:31,567 --> 00:09:33,536
OUT PLATELETS AND LOOK FOR TUMOR

243
00:09:33,536 --> 00:09:33,770
GROWTH.

244
00:09:33,770 --> 00:09:36,506
THIS IS JUST THE CONFIRMATION WE

245
00:09:36,506 --> 00:09:37,340
CAN TRANSFORM PLATELETS AND

246
00:09:37,340 --> 00:09:39,142
INDEED WE SEE THE TUMORS MORE IF

247
00:09:39,142 --> 00:09:43,212
WE USE A C, DID 40 LIGAND KNOCK

248
00:09:43,212 --> 00:09:44,847
OUT PLATELET AS A TRANSFER

249
00:09:44,847 --> 00:09:45,681
ITSELF.

250
00:09:45,681 --> 00:09:48,484
WHAT IS THE DOWN STREAM EFFECT,

251
00:09:48,484 --> 00:09:50,620
THE CD4 LIGAND BASICALLY

252
00:09:50,620 --> 00:09:52,021
ACTIVATES KRRK DT-CELLS, WE CAN

253
00:09:52,021 --> 00:09:54,891
SEE THIS HERE, IF WE PLOK THIS

254
00:09:54,891 --> 00:09:57,193
T-CELL,--SORRY IF WEB CONNECTED

255
00:09:57,193 --> 00:10:00,963
BLOCK THE CELLS MAKE LESS

256
00:10:00,963 --> 00:10:02,565
INTERFERON-GAMMA.

257
00:10:02,565 --> 00:10:05,334
IF YOU DEPLETE--IF WE DEPLETE

258
00:10:05,334 --> 00:10:08,838
CD8 T-CELLS THEY MAKE LESS CD6,

259
00:10:08,838 --> 00:10:11,507
AND SAME IF WE TAKE A CD40

260
00:10:11,507 --> 00:10:12,775
LIGAND KNOCK OUT PLATELET.

261
00:10:12,775 --> 00:10:15,912
SO THE NEXT QUESTION IS HOW DOES

262
00:10:15,912 --> 00:10:17,513
THIS WORKING, WHY DOES THE PLATE

263
00:10:17,513 --> 00:10:19,515
HAVE SO MUCH CDLIGAND SO WE WENT

264
00:10:19,515 --> 00:10:22,018
ARK HEAD AND STARTED TO

265
00:10:22,018 --> 00:10:24,120
LOOK--AND THEY HAVE CARIO SIGHTS

266
00:10:24,120 --> 00:10:26,456
IN THE PRODUCTION OF CD4

267
00:10:26,456 --> 00:10:26,789
LIGANDS.

268
00:10:26,789 --> 00:10:29,358
FROM THIS WE USE PLASMA THAT ARE

269
00:10:29,358 --> 00:10:32,328
ON AN NORMAL DIET OR MCD DIET

270
00:10:32,328 --> 00:10:35,064
AND WE SHOW THAT THOSE PLATELETS

271
00:10:35,064 --> 00:10:36,466
OR THOSE MEGACARRIER SITES THAT

272
00:10:36,466 --> 00:10:37,700
ARE ENCUE BAITED FROM PLASMA

273
00:10:37,700 --> 00:10:40,837
FROM THE MOUSE ON AN MCD DIET

274
00:10:40,837 --> 00:10:42,238
ARE INDEED EPIRICHED IN KRRK D40

275
00:10:42,238 --> 00:10:47,710
LIGAND AND YOU CAN SEE HERE

276
00:10:47,710 --> 00:10:48,878
CORRESPONDING IMAGING.

277
00:10:48,878 --> 00:10:50,847
THIS AFFECT IS DEPEND END ON

278
00:10:50,847 --> 00:10:52,181
IL12.

279
00:10:52,181 --> 00:10:55,084
IF YOU BLOCK IL12, YOU SEE A

280
00:10:55,084 --> 00:10:57,553
REDUCTION OF CD40 LIGAND IN THE

281
00:10:57,553 --> 00:10:57,820
MEGASITES.

282
00:10:57,820 --> 00:10:59,956
AGAIN, WE CAN SEE THE SAME ALSO

283
00:10:59,956 --> 00:11:03,860
IF WE INHIBIT THE PLATELET

284
00:11:03,860 --> 00:11:05,862
FUNCTION AND AS SHOWN HERE,

285
00:11:05,862 --> 00:11:08,931
SHOWN HERE, AND INTERESTINGLY,

286
00:11:08,931 --> 00:11:11,467
THE PLATELETS ARE NOT ONLY

287
00:11:11,467 --> 00:11:12,635
PRODUCED BY MEGACARIO CITES IN

288
00:11:12,635 --> 00:11:14,103
THE BONE MARROW BUT THERE'S ALSO

289
00:11:14,103 --> 00:11:15,838
A FAIR NUMBER OF MEGACARIO CITES

290
00:11:15,838 --> 00:11:17,773
IN THE LUNG AND YOU CAN SEE THAT

291
00:11:17,773 --> 00:11:20,610
THOSE ARE JUST EQUALLY WELL

292
00:11:20,610 --> 00:11:24,747
EQUIPPED TO PRODUCE CD40 LIGAND

293
00:11:24,747 --> 00:11:25,515
ENRICHED PLATELETS.

294
00:11:25,515 --> 00:11:28,818
SO LET ME SUMMARIZE WHAT I'VE

295
00:11:28,818 --> 00:11:31,754
SHOWN YOU HERE--THIS IS NOT

296
00:11:31,754 --> 00:11:33,456
BEHAVING SO I CAN'T USE THE

297
00:11:33,456 --> 00:11:34,023
POINTER FOR YOU.

298
00:11:34,023 --> 00:11:35,825
SO WHAT I CAN SHOW YOU HERE IS

299
00:11:35,825 --> 00:11:44,901
THAT IN THE CONTEXT OF FATTY

300
00:11:44,901 --> 00:11:47,837
LIVER DISEASE, THERE IS A

301
00:11:47,837 --> 00:11:50,439
RELEASE TO IL12 THAT SIGNALS TO

302
00:11:50,439 --> 00:11:52,308
THE BONE AND MEGASIGHTS IN THE

303
00:11:52,308 --> 00:11:53,709
BONE TO MAKE PLATELETS THAT ARE

304
00:11:53,709 --> 00:11:55,845
ENRICH INDEED C, DID 40 LIGAND.

305
00:11:55,845 --> 00:11:57,013
THIS PLATELETS GO BACK INTO THE

306
00:11:57,013 --> 00:11:58,681
LIVER IN THE CONTEXT OF FATTY

307
00:11:58,681 --> 00:12:02,618
LIVER DISEASE, SAY I ACTIVATED

308
00:12:02,618 --> 00:12:08,891
THROUGH A P2 Y12 MECHANISM,

309
00:12:08,891 --> 00:12:12,528
REMEMBER,OOSE INHIBITING P2 Y12,

310
00:12:12,528 --> 00:12:14,263
IT ACTIVATES CD40 LIGAND ANDS

311
00:12:14,263 --> 00:12:15,665
THAT BLOCKS TUMOR GROWTH.

312
00:12:15,665 --> 00:12:17,533
NOW LET'S SWITCH TO THE

313
00:12:17,533 --> 00:12:17,833
MICROBIOME.

314
00:12:17,833 --> 00:12:19,869
I WILL SHOW YOU A STUDY WHERE WE

315
00:12:19,869 --> 00:12:20,603
FINISHED RECENTLY WHERE WE LOOK

316
00:12:20,603 --> 00:12:23,673
AT THE EFFECT OF THE GUT

317
00:12:23,673 --> 00:12:25,841
MICROBIOME AND HOW THE GUT

318
00:12:25,841 --> 00:12:28,444
MICROBIOME IN THE LIVER, SHAPES

319
00:12:28,444 --> 00:12:30,079
ANTITUMOR IMMUNITY AND WITH THIS

320
00:12:30,079 --> 00:12:32,715
WE WENT NOW AND LOOK AT BILLIARY

321
00:12:32,715 --> 00:12:33,249
CANCER.

322
00:12:33,249 --> 00:12:37,186
SO THIS IS A TUMOR THAT GROWS

323
00:12:37,186 --> 00:12:41,824
FROM IN THE BIODUCT AWELL AS IN

324
00:12:41,824 --> 00:12:43,359
THE IMAWL BLADDER AND THERE ARE

325
00:12:43,359 --> 00:12:50,666
CERTAIN RISK FACTORS AND PRIMARY

326
00:12:50,666 --> 00:12:53,469
CHOL ANGITEIS, AND BOWEL

327
00:12:53,469 --> 00:12:55,738
DISEASE, BECAUSE PATIENTS WITH

328
00:12:55,738 --> 00:12:58,074
THIS DISEASE HAVE A LOWERED GUT

329
00:12:58,074 --> 00:12:59,408
MICROBIOME, SO IF THAT IS THE

330
00:12:59,408 --> 00:13:01,110
CASE WE SHOULD LOOK INTO THIS IN

331
00:13:01,110 --> 00:13:02,678
MORE DETAIL AND SEE HOW THIS

332
00:13:02,678 --> 00:13:03,245
APPLIES TO A PHOSPHORYLATED

333
00:13:03,245 --> 00:13:04,447
MODEL AND IF YOU CAN BETTER

334
00:13:04,447 --> 00:13:07,850
UNDERSTAND THE MECHANISM FOR

335
00:13:07,850 --> 00:13:08,384
THIS.

336
00:13:08,384 --> 00:13:12,288
INDEED IF WE INDUCE PSC IN MICE,

337
00:13:12,288 --> 00:13:19,562
WE SEE A LEAKY GUT, WE SEE THE

338
00:13:19,562 --> 00:13:22,031
FOUNDATION OF OCCRUDIN IN A

339
00:13:22,031 --> 00:13:23,165
GRAPHS, USING A BIODUCT

340
00:13:23,165 --> 00:13:24,367
LOCATION, IF THIS HAPPENS WE

341
00:13:24,367 --> 00:13:28,170
ALSO SEE AN INCREASE OF IL17 IN

342
00:13:28,170 --> 00:13:31,040
THE SMALL INTESTINE, WE SEE AN

343
00:13:31,040 --> 00:13:33,843
INCREASE OF SRNA AS A BACTERIAL

344
00:13:33,843 --> 00:13:36,112
READ OUT IN TRANSLOCATION IN THE

345
00:13:36,112 --> 00:13:38,247
PORTAL VEIN, AND WE IF WE LOOK

346
00:13:38,247 --> 00:13:40,182
AT PEASHT SAMPLES WITH

347
00:13:40,182 --> 00:13:42,084
CIRRHOSIS, WE CAN FIND

348
00:13:42,084 --> 00:13:42,985
POTENTIALLY BACTERIA IN THE

349
00:13:42,985 --> 00:13:43,886
GROWTH.

350
00:13:43,886 --> 00:13:46,255
WHAT HAPPENS IN THE LIVER.

351
00:13:46,255 --> 00:13:47,657
WE LOOKED AT DIFFERENT IMMUNE

352
00:13:47,657 --> 00:13:50,092
CELLS AND WE FOUND IF WE INDUCE

353
00:13:50,092 --> 00:13:53,562
PSC, IN THIS CASE, WE USE MDRD2

354
00:13:53,562 --> 00:13:55,464
KNOCK OUT, THERE'S AN INCREASE

355
00:13:55,464 --> 00:13:57,400
IN SO CALLED MYELOID DEPRESSOR

356
00:13:57,400 --> 00:13:59,301
CELLS WHICH WE CAN FURTHER

357
00:13:59,301 --> 00:14:02,138
CHARACTERIZE AND DIVIDE INTO

358
00:14:02,138 --> 00:14:03,105
MONOSITTIC AND [INDISCERNIBLE]

359
00:14:03,105 --> 00:14:05,141
WHICH ARE INCREASED IN THE LIVER

360
00:14:05,141 --> 00:14:07,943
JUST BY INDUCING THE CIRRHOSIS

361
00:14:07,943 --> 00:14:08,944
IN THE LIVER.

362
00:14:08,944 --> 00:14:12,948
IT ALSO APPLIES TO THE SECOND

363
00:14:12,948 --> 00:14:15,317
MODEL, THIS MDSCs EXPRESS

364
00:14:15,317 --> 00:14:16,318
CXCR2.

365
00:14:16,318 --> 00:14:19,221
A CHEMOKINE RECEPTOR THAT IS

366
00:14:19,221 --> 00:14:20,322
SPECIFIC FOR CXCR1.

367
00:14:20,322 --> 00:14:24,160
AND INDEED WE ACTUALLY FIND

368
00:14:24,160 --> 00:14:30,066
INCREASED CXCR 1 BOTH WHEN WE

369
00:14:30,066 --> 00:14:31,867
INDUCE SCLEROSIS AND CHOL

370
00:14:31,867 --> 00:14:35,237
ANGITEIS, AND BOTH LEADING TO AN

371
00:14:35,237 --> 00:14:40,309
INCREASE OF 16 SRNA AND BEING A

372
00:14:40,309 --> 00:14:41,944
RISK FACTOR FOR CHOL ANGIAL

373
00:14:41,944 --> 00:14:43,145
CARCINOMA EMPLOY IF YOU BLOOK

374
00:14:43,145 --> 00:14:47,583
THIS, IN THIS CASE WE USE AN

375
00:14:47,583 --> 00:14:48,818
ANTIBODY AGAINST CXCR1, IN ALL

376
00:14:48,818 --> 00:14:51,854
OF THESE CASES, WE REDUCE THE

377
00:14:51,854 --> 00:14:55,091
NUMBER OF THIS IMMUNOSUPPRESSIVE

378
00:14:55,091 --> 00:14:55,424
MYELOID CELLS.

379
00:14:55,424 --> 00:14:59,962
AND BY DOING SO, AND THIS

380
00:14:59,962 --> 00:15:03,299
MECHANISM IS DEPENDENT ON TLR4

381
00:15:03,299 --> 00:15:04,166
EXPRESSION ON HEPATOCYTES AS YOU

382
00:15:04,166 --> 00:15:07,336
CAN SEE ON THE LOWER RIGHT.

383
00:15:07,336 --> 00:15:10,473
SO THIS IS THOT REALLY A CANCER

384
00:15:10,473 --> 00:15:11,974
MODEL YET, SO WHAT HAVE I SHOWN

385
00:15:11,974 --> 00:15:13,509
YOU SO FAR IN WHAT I'VE SHOWN

386
00:15:13,509 --> 00:15:15,544
YOU IS IN THE CONTEXT OF LIVER

387
00:15:15,544 --> 00:15:18,781
CIRRHOSIS, THERE A LEAKY GUT,

388
00:15:18,781 --> 00:15:21,851
WHICH LEADS TO HEPATOCYTES

389
00:15:21,851 --> 00:15:23,686
MAKING CXCR1, AND THEN THE IPT

390
00:15:23,686 --> 00:15:26,288
GREATER CREASE OF THE CXCR1

391
00:15:26,288 --> 00:15:29,191
INCREASE IN THE DISEASE, AND

392
00:15:29,191 --> 00:15:30,693
THIS MECHANISM IS TLR4, AND WE

393
00:15:30,693 --> 00:15:34,263
CAN SHOW THIS IS DEPENDENT ON

394
00:15:34,263 --> 00:15:36,198
THE NEGATIVE BACTERIA AND AGAIN

395
00:15:36,198 --> 00:15:39,401
THIS ONLY EXPLAINS CIRRHOSIS AND

396
00:15:39,401 --> 00:15:41,170
MDCs BUT NOT A TUMOR MODEL SO

397
00:15:41,170 --> 00:15:43,906
WE NEXT WENT ARK HEAD AND

398
00:15:43,906 --> 00:15:45,508
COMBINED THIS WITH THE TUMOR

399
00:15:45,508 --> 00:15:45,841
MODEL.

400
00:15:45,841 --> 00:15:49,378
SO FOR THIS AGAIN, WE USE THE

401
00:15:49,378 --> 00:15:51,480
[INDISCERNIBLE] AND WE PERFORM

402
00:15:51,480 --> 00:15:52,181
HYDRODYNAMIC INYEKS AND YOU CAN

403
00:15:52,181 --> 00:15:54,717
SEE IF WE DO THIS, THESE MICE

404
00:15:54,717 --> 00:15:57,319
ARE MORE LIKELY TO DEVELOP

405
00:15:57,319 --> 00:15:57,553
TUMORS.

406
00:15:57,553 --> 00:16:02,892
CAN YOU SEE THE MICROSCOPIC

407
00:16:02,892 --> 00:16:04,894
PICTURES AND MICE WITH PSC, IN A

408
00:16:04,894 --> 00:16:06,996
SECOND MODEL WHERE WE USE THE

409
00:16:06,996 --> 00:16:08,998
MDR2 KNOCKOUT MICE, YOU SEE THE

410
00:16:08,998 --> 00:16:09,665
SAME THING AGAIN.

411
00:16:09,665 --> 00:16:11,834
NOW IS THIS AGAIN DEPENDENT ON

412
00:16:11,834 --> 00:16:14,236
CHANGES IN THE GUT MICROBIOME

413
00:16:14,236 --> 00:16:17,406
AND IS THIS DEPENDENT ON

414
00:16:17,406 --> 00:16:19,575
POLYMORPHIN AMERICA DSCs, IF

415
00:16:19,575 --> 00:16:24,580
WE DEPLETE THESE MDSCs, USING

416
00:16:24,580 --> 00:16:30,119
AN ANTIBODY AGAINST LYSX1, OR IF

417
00:16:30,119 --> 00:16:35,090
WE OVER EXPRESS CXCL1, CAN YOU

418
00:16:35,090 --> 00:16:40,496
SEE IT AND INDEED THIS CONTROLS

419
00:16:40,496 --> 00:16:40,830
TUMOR GROWTH.

420
00:16:40,830 --> 00:16:41,964
NOW HOW CAN WE SHOW THIS IS

421
00:16:41,964 --> 00:16:45,000
RELATED TO THE GUT MICROBIOME?

422
00:16:45,000 --> 00:16:49,839
THE WAY WE DID THIS WAS BY USING

423
00:16:49,839 --> 00:16:51,941
OR CONDUCTING FMT STUDIES.

424
00:16:51,941 --> 00:16:56,545
SO IN THIS CASE, WE CONDUCT

425
00:16:56,545 --> 00:16:57,613
STOOL SAMPLES FROM MICE THAT

426
00:16:57,613 --> 00:17:04,954
HAVE BEEN TREATED WITH

427
00:17:04,954 --> 00:17:06,021
ANTIBIOTICS WITH VANCOMYCIN, OR

428
00:17:06,021 --> 00:17:07,923
[INDISCERNIBLE], AND THE

429
00:17:07,923 --> 00:17:09,391
MECHANISM WE REPORT IS TLR

430
00:17:09,391 --> 00:17:12,561
DEPENDENT AND INDEED IF WE TREAT

431
00:17:12,561 --> 00:17:15,764
THESE MICE WITH NEOMICE IN, WE

432
00:17:15,764 --> 00:17:18,033
SEE FEWER TUMORS SUGGIESTING

433
00:17:18,033 --> 00:17:19,935
THIS MECHANISM OF TUMOR FROAGHT

434
00:17:19,935 --> 00:17:21,403
DEPENDENT ON THIS TLR4 AND WE

435
00:17:21,403 --> 00:17:23,505
CAN SHOW THIS ALSO USING

436
00:17:23,505 --> 00:17:25,908
CONDITIONAL KNOCKOUT MICE WHERE

437
00:17:25,908 --> 00:17:28,477
WE ACTUALLY ON KNOCK OUT THE

438
00:17:28,477 --> 00:17:31,013
TLR4 MOLECULE ON HEPATOCYTE.

439
00:17:31,013 --> 00:17:32,081
YOU CAN SEE THIS ON THE LOWER

440
00:17:32,081 --> 00:17:33,616
GRAPH WITH THE BLUE BAR.

441
00:17:33,616 --> 00:17:37,720
THERE IS FEWER TUMORS AND THEN

442
00:17:37,720 --> 00:17:44,326
WE CAN RESCUE THIS IF WE

443
00:17:44,326 --> 00:17:45,261
OVEREXPRESS CXCL1.

444
00:17:45,261 --> 00:17:48,564
THE DOWN STREAM CELL THAT IS

445
00:17:48,564 --> 00:17:50,866
AFFECTED IS MAINLY AN ENCASE O.

446
00:17:50,866 --> 00:17:52,568
NOW WHAT IS THE MECHANISM THAT

447
00:17:52,568 --> 00:17:54,737
WE PROPOSE HERE, SO, THERE IS

448
00:17:54,737 --> 00:17:57,907
THIS INTERACTION THAT WE CALL

449
00:17:57,907 --> 00:18:00,943
THE GUT LIVER ACCESS AND UNDER

450
00:18:00,943 --> 00:18:04,513
NORMAL CIRCUMSTANCES YOU HAVE

451
00:18:04,513 --> 00:18:07,016
THE LIVER RELEASING AND TALKING

452
00:18:07,016 --> 00:18:10,419
TO THE GUT AS WELL THE AS GUT

453
00:18:10,419 --> 00:18:11,820
TALKING TO THE LIVER.

454
00:18:11,820 --> 00:18:15,824
ONCE YOU DEVELOP FIBROSIS OR

455
00:18:15,824 --> 00:18:18,160
CIRRHOSIS, WHAT HAPPENS IS THAT

456
00:18:18,160 --> 00:18:19,962
YOU WILL ACTUALLY HAVE CHANGES

457
00:18:19,962 --> 00:18:22,264
IN BILE, AND YOU WILL HAVE

458
00:18:22,264 --> 00:18:24,967
DISBIOSEIS, SO THE GUT

459
00:18:24,967 --> 00:18:26,435
MICROBIOME IS CHANGING.

460
00:18:26,435 --> 00:18:27,236
WE STUDIED THIS.

461
00:18:27,236 --> 00:18:28,971
I DIDN'T SHOW YOU THIS FOR TIME

462
00:18:28,971 --> 00:18:29,438
REASON.

463
00:18:29,438 --> 00:18:31,874
BUT WHAT I SHOWED WAS THE LEAKY

464
00:18:31,874 --> 00:18:33,208
GUT, REMEMBER THE HISTOLOGICAL

465
00:18:33,208 --> 00:18:35,978
PICTURES AND THE INCREASE OF LPS

466
00:18:35,978 --> 00:18:39,481
AND 16 SRNA, BACTERIA CAN GO AND

467
00:18:39,481 --> 00:18:43,686
IMET INTO THE GUT EPITHELIUM AND

468
00:18:43,686 --> 00:18:46,121
THEN GO THROUGH THE PORTER VEIN,

469
00:18:46,121 --> 00:18:49,858
ONCE THEY REACH THE LIVER, THEY

470
00:18:49,858 --> 00:18:51,560
INDUCE CXCL1 CREATION BY

471
00:18:51,560 --> 00:18:54,663
HEPATOCYTES, THIS IS THROUGH A

472
00:18:54,663 --> 00:18:56,465
TLR4 DEPENDENT MECHANISM,

473
00:18:56,465 --> 00:19:00,369
LEADING TO ARK KIEWMULATION OF

474
00:19:00,369 --> 00:19:01,136
IMMUNOSUPPRESSIVE CXCLPOSITIVE

475
00:19:01,136 --> 00:19:05,774
MDSCs WHICH IN TURN BLOCK NK

476
00:19:05,774 --> 00:19:12,314
CELL FUNCTION AND THEREBY

477
00:19:12,314 --> 00:19:13,215
PROMOTE TUMOR GROWTH.

478
00:19:13,215 --> 00:19:18,253
SO THIS IS 1 STUDY WHERE YOU

479
00:19:18,253 --> 00:19:19,588
BASICALLY--SEE AGAIN HOW THE

480
00:19:19,588 --> 00:19:20,789
ENVIRONMENT, THE LIVER SPECIFIC

481
00:19:20,789 --> 00:19:23,392
ENVIRONMENT IS AFFECTED BY THE

482
00:19:23,392 --> 00:19:24,994
GUT MICROBIOME BUT WHAT IS

483
00:19:24,994 --> 00:19:26,228
ACTUALLY THE LIVER SPECIFIC

484
00:19:26,228 --> 00:19:28,097
ENVIRONMENT AND I THINK THIS IS

485
00:19:28,097 --> 00:19:31,967
PROBABLY THE MOST INTERESTING

486
00:19:31,967 --> 00:19:34,803
PART, IF YOU WORK IN LIVER

487
00:19:34,803 --> 00:19:37,206
CANCER IMMUNOLOGY WHICH IS THAT

488
00:19:37,206 --> 00:19:38,107
THE LIVER IMMUNE

489
00:19:38,107 --> 00:19:40,976
MICROENVIRONMENT IS VERY, VERY

490
00:19:40,976 --> 00:19:41,243
DISTINCT.

491
00:19:41,243 --> 00:19:43,846
WHICH BRINGS ME TO THE NEXT

492
00:19:43,846 --> 00:19:44,346
TOPIC, THE LIVER IMMUNE

493
00:19:44,346 --> 00:19:45,681
MICROENVIRONMENT AND FOR THOSE

494
00:19:45,681 --> 00:19:47,383
OF YOU WHO DON'T LIKE T-CELLS

495
00:19:47,383 --> 00:19:48,384
AND DO NOT WORK WITH IMMUNE

496
00:19:48,384 --> 00:19:50,119
CELLS ALL THE TIME, LET ME

497
00:19:50,119 --> 00:19:53,422
INTRODUCE YOU WHAT WE ARE

498
00:19:53,422 --> 00:19:54,990
TALKING ABOUT.

499
00:19:54,990 --> 00:19:58,127
SO YOU ALL KNOW CD8 T-CELLS

500
00:19:58,127 --> 00:20:00,062
PROBABLY THAT RECOGNIZE MHC

501
00:20:00,062 --> 00:20:04,133
CALCIUM 1 MOLECULE AND AN

502
00:20:04,133 --> 00:20:06,735
ANTIIEN DERIVE FRIDAY

503
00:20:06,735 --> 00:20:07,603
INTRACELLULAR PROTEINS AND

504
00:20:07,603 --> 00:20:10,506
RECOGNIZE THEM ON AN MHC

505
00:20:10,506 --> 00:20:11,607
MOLECULE EMPLOY NOW ARK PART

506
00:20:11,607 --> 00:20:12,975
FROM THESE CLASSICAL T-CELLS WE

507
00:20:12,975 --> 00:20:17,312
FIND IN THE LIVER, A NUMBER OF

508
00:20:17,312 --> 00:20:19,314
OTHER IMMUNE CELLS.

509
00:20:19,314 --> 00:20:23,852
WE FIND GAMMADELTA T-CELLS, WE

510
00:20:23,852 --> 00:20:24,953
FIND NKT-CELLS.

511
00:20:24,953 --> 00:20:33,996
THIS IS KILLING ME HERE.

512
00:20:33,996 --> 00:20:39,134
SO WE FIND NKT CELLS AND WE FIND

513
00:20:39,134 --> 00:20:41,370
MAIT CELLS, THIS RECOGNIZES THE

514
00:20:41,370 --> 00:20:43,572
MOLECULE, RECOGNIZES THE FLIEK O

515
00:20:43,572 --> 00:20:46,375
LIPID, MAIT CELLS WHICH

516
00:20:46,375 --> 00:20:49,311
RECOGNIZE RIBOFLAVIN WHICH IS A

517
00:20:49,311 --> 00:20:52,648
VITAMIN B METABOLITE AND A

518
00:20:52,648 --> 00:20:53,749
GAMMADELTA T-CELL WHICH

519
00:20:53,749 --> 00:20:55,651
RECOGNIZE FOSTER NURSED FOCUSED

520
00:20:55,651 --> 00:20:55,951
ON ANTIGENS.

521
00:20:55,951 --> 00:20:57,986
APART FROM THESE THERE ARE

522
00:20:57,986 --> 00:20:59,521
RELATIVELY 1 CELLS AND OBVIOUSLY

523
00:20:59,521 --> 00:21:01,023
I ALREADY ALLUDED A LITTLE BIT

524
00:21:01,023 --> 00:21:03,392
TO THESE NK CELLS.

525
00:21:03,392 --> 00:21:05,694
NOW THIS MAY BE STILL STRAIGHT

526
00:21:05,694 --> 00:21:06,862
FORWARD, UNFORTUNATELY I HAVE TO

527
00:21:06,862 --> 00:21:08,697
TELL YOU IT IS NOT THAT STRAIGHT

528
00:21:08,697 --> 00:21:10,532
FORWARD AS YOU THINK BECAUSE WE

529
00:21:10,532 --> 00:21:12,534
CAN SUBCATEGORIZE THESE CELLS ON

530
00:21:12,534 --> 00:21:20,876
TRANSCRIPTION FACTORS A LITTLE

531
00:21:20,876 --> 00:21:21,477
BIT MORE.

532
00:21:21,477 --> 00:21:23,479
BUT WHAT I WOULD REALLY LIKE TO

533
00:21:23,479 --> 00:21:24,780
TALK ABOUT IN THE REST OF MY

534
00:21:24,780 --> 00:21:26,515
TIME HERE IS BASICALLY I WOULD

535
00:21:26,515 --> 00:21:28,417
LIKE TO TALK ABOUT REGULATORY

536
00:21:28,417 --> 00:21:29,518
T-CELLS TOWARDS THE END OF MY

537
00:21:29,518 --> 00:21:33,055
TALK AND BEFORE I GET THERE,

538
00:21:33,055 --> 00:21:34,590
ABOUT MAITs, WHICH ARE VERY

539
00:21:34,590 --> 00:21:37,392
ABUNDANT IN THE LIVER AND CAN AS

540
00:21:37,392 --> 00:21:45,467
I WILL SHOW YOU  EXERT VERY

541
00:21:45,467 --> 00:21:46,869
POTENT IMMUNITY AS I HAVE SHOWN

542
00:21:46,869 --> 00:21:48,036
YOU IN PRECLINICAL MOUSE MODELS.

543
00:21:48,036 --> 00:21:50,339
SO WE DECIDED TO STUDY THESE

544
00:21:50,339 --> 00:21:52,341
MAITs WHICH ARE VERY COMMON

545
00:21:52,341 --> 00:21:53,675
AND ABUNDANT IN MOUSE LIVERS IN

546
00:21:53,675 --> 00:21:54,510
MORE DETAIL.

547
00:21:54,510 --> 00:21:57,379
THE WAY WE DID THIS IS BASICALLY

548
00:21:57,379 --> 00:21:59,748
SHOWN HERE, SO, WE SET UP A

549
00:21:59,748 --> 00:22:00,549
COLLABORATION WITH OUR

550
00:22:00,549 --> 00:22:03,485
COLLEAGUES AT JOARMING TOWN, THE

551
00:22:03,485 --> 00:22:05,587
TRANSPLANT CENTER, AND THEY

552
00:22:05,587 --> 00:22:07,956
EXPLANTED LIVERS AND WE WERE

553
00:22:07,956 --> 00:22:09,925
ABLE TO CLICK HEART ATTACK

554
00:22:09,925 --> 00:22:12,327
CC SAMPLES FROM THESE PATIENTS.

555
00:22:12,327 --> 00:22:13,729
WE WERE ABLE TO COLLECT A PIECE

556
00:22:13,729 --> 00:22:15,531
THAT BASIC LYE CONTAINS THE

557
00:22:15,531 --> 00:22:18,066
ADJACENT LIVER, THE TUMOR

558
00:22:18,066 --> 00:22:19,535
BORDER, AND THE TUMOR CORE AND

559
00:22:19,535 --> 00:22:22,638
WE USED THIS TO ISOLATE

560
00:22:22,638 --> 00:22:24,406
MONONUCLEAR CELLS AND SORT THEM

561
00:22:24,406 --> 00:22:26,041
BUT MORE IMPORTANTLY WE USE THEM

562
00:22:26,041 --> 00:22:34,550
FOR TISSUE EMBEDDING AND

563
00:22:34,550 --> 00:22:35,651
STAINING.

564
00:22:35,651 --> 00:22:37,085
THEN WE PERFORMED CODE

565
00:22:37,085 --> 00:22:38,720
EXPECTATIONS SAMPLING USING

566
00:22:38,720 --> 00:22:40,322
SINGLE CELL ANTIBODIES AND

567
00:22:40,322 --> 00:22:43,192
SINGLE CELL FLOW CYTOMETRY AND

568
00:22:43,192 --> 00:22:45,827
THE SINGLE CELL DATA WAS FURTHER

569
00:22:45,827 --> 00:22:49,097
STUDIED USING BIOINFORMATIC

570
00:22:49,097 --> 00:22:54,203
ANALYSIS.

571
00:22:54,203 --> 00:22:56,505
NOW THIS DATA THIS DATA IS

572
00:22:56,505 --> 00:22:58,507
INTERESTING, BUT WE ONLY USE IT

573
00:22:58,507 --> 00:22:59,708
TO GEPERATE A HYPOTHESIS AND

574
00:22:59,708 --> 00:23:01,109
DECIDED WE WILL LIKE TO

575
00:23:01,109 --> 00:23:02,277
VALENTINED DIADIC FINDINGS

576
00:23:02,277 --> 00:23:03,445
TRUSTEES THIS USING DIFFERENT

577
00:23:03,445 --> 00:23:06,081
METHODS SO WE USED PATIENTS WE

578
00:23:06,081 --> 00:23:08,116
HAD TREATED WITH IMMUNE CHECK

579
00:23:08,116 --> 00:23:10,686
INHIBITORS AND SINGLE CELL DATA.

580
00:23:10,686 --> 00:23:12,354
WE VERIFIED SOME OF THE DATA

581
00:23:12,354 --> 00:23:14,056
USING DATA FROM PATIENT COHORTS

582
00:23:14,056 --> 00:23:15,857
THAT WERE AVAILABLE AND LOOKING

583
00:23:15,857 --> 00:23:18,293
AT SURVIVAL ANALYSIS, BUT MOST

584
00:23:18,293 --> 00:23:20,462
IMPORTANTLY WE ALSO PERFORMED

585
00:23:20,462 --> 00:23:25,133
FUNCTIONAL STUDIES IN MICE TO

586
00:23:25,133 --> 00:23:28,103
REALLY VERIFY WHAT WE SEE USING

587
00:23:28,103 --> 00:23:30,305
THIS HIGHLY COMPLEX DATA REALLY

588
00:23:30,305 --> 00:23:38,247
TRANSLATES INTO THE MECHANISM SO

589
00:23:38,247 --> 00:23:39,748
NOW NEXT DATA, I HAVEN'T DONE

590
00:23:39,748 --> 00:23:41,583
ANYTHING, BUT THIS IS A COMPLEX

591
00:23:41,583 --> 00:23:42,618
PROJECT THAT REQUIRED A LOT OF

592
00:23:42,618 --> 00:23:47,589
COLLABORATION AND WE ARE THE KEY

593
00:23:47,589 --> 00:23:49,658
PLAYERS FOR THIS WORK IT

594
00:23:49,658 --> 00:23:52,160
STARTING WITH WILL ALEX CORMA AT

595
00:23:52,160 --> 00:23:53,595
GEORGE TOWN, WE HAD

596
00:23:53,595 --> 00:23:58,700
[INDISCERNIBLE] WHO HELPED US

597
00:23:58,700 --> 00:24:00,269
WITH CODEX AND [INDISCERNIBLE],

598
00:24:00,269 --> 00:24:03,538
AND IN MY GROUP [INDISCERNIBLE]

599
00:24:03,538 --> 00:24:04,106
WHO LED THIS ROG ECTOMYOSIN.

600
00:24:04,106 --> 00:24:08,243
SO IF YOU LOOK AT MAITs, THE

601
00:24:08,243 --> 00:24:10,479
FIRST THING WE NOTICE IS IF WE

602
00:24:10,479 --> 00:24:13,615
COMPARE THE NONTUMOR VERSUS

603
00:24:13,615 --> 00:24:14,850
TUMOR TISSUE, THE MAITs DON'T

604
00:24:14,850 --> 00:24:16,718
MAKE IT INTO THE TUMOR.

605
00:24:16,718 --> 00:24:19,988
THERE'S A DECREASE IN

606
00:24:19,988 --> 00:24:20,322
INFILTRATION.

607
00:24:20,322 --> 00:24:22,791
WE SEE EXACTLY THE SAME IN MICE.

608
00:24:22,791 --> 00:24:26,461
YOU SEE HERE THE DATA THE

609
00:24:26,461 --> 00:24:30,299
NONDATA VERSUS TUMOR, FEWER M,

610
00:24:30,299 --> 00:24:32,634
ITs, IN THE TUMOR, IT'S NOT

611
00:24:32,634 --> 00:24:34,336
THAT THEY'RE LESS FREQUENT,

612
00:24:34,336 --> 00:24:36,705
THEY'RE ALSO LESS FUNCTIONAL AS

613
00:24:36,705 --> 00:24:38,206
AN EXAMPLE OF INTERFERON-GAMMA.

614
00:24:38,206 --> 00:24:42,077
SO THIS IS OBVIOUSLY SOMETHING

615
00:24:42,077 --> 00:24:43,679
THAT YOU KNOW THAT WE WOULD NOT

616
00:24:43,679 --> 00:24:44,079
NECESSARILY LIKE.

617
00:24:44,079 --> 00:24:47,949
SO LET ME JUST SUMMARIZE BEEF

618
00:24:47,949 --> 00:24:48,850
BRAE, MAIT CELLS ARE ABUB ANT IN

619
00:24:48,850 --> 00:24:50,152
THE LIVER DATA, I HAVE NOT SHOWN

620
00:24:50,152 --> 00:24:52,154
YOU ALL THE DATA, THIS IS SOME

621
00:24:52,154 --> 00:24:53,588
OF THIS, WE WERE ABLE TO MAKE

622
00:24:53,588 --> 00:24:54,890
SURE IT CORRELATES WITH THE

623
00:24:54,890 --> 00:24:56,391
PATIENT'S OUTCOME, I'VE SHOWN

624
00:24:56,391 --> 00:24:59,361
YOU THEY CAN IMPAIR--ACTUALLY I

625
00:24:59,361 --> 00:25:01,363
HAVEN'T SHOWN YOU THAT THEY

626
00:25:01,363 --> 00:25:01,963
IMPAIR TUMOR FROAGHT, BUT YOU

627
00:25:01,963 --> 00:25:03,031
HAVE TO BELIEVE IT, WE HAVE DONE

628
00:25:03,031 --> 00:25:05,534
THE STUDIES AND THEY ARE

629
00:25:05,534 --> 00:25:07,502
CHARACTERIZED BY FILTRATION INTO

630
00:25:07,502 --> 00:25:08,437
LIVER TUMORS INCREASING

631
00:25:08,437 --> 00:25:11,340
DYSFUNCTION AND LOSS OF TOXICITY

632
00:25:11,340 --> 00:25:13,875
WITH WITHIN THE HCC TUMOR

633
00:25:13,875 --> 00:25:14,176
ENVIRONMENT.

634
00:25:14,176 --> 00:25:16,278
SO THIS BRINGS UP THE QUESTION,

635
00:25:16,278 --> 00:25:16,878
WHY IS THIS?

636
00:25:16,878 --> 00:25:19,014
WHAT CAUSES THIS INNATE CELL

637
00:25:19,014 --> 00:25:19,314
DYSFUNCTION?

638
00:25:19,314 --> 00:25:20,282
WHY DON'T THEY GO INTO THE

639
00:25:20,282 --> 00:25:22,084
TUMORS AND WHAT MAKES THEM

640
00:25:22,084 --> 00:25:25,587
DYSFUNCTIONAL IN SO IN ORDER TO

641
00:25:25,587 --> 00:25:29,257
DO THIS WE DECIDED TO DO THE

642
00:25:29,257 --> 00:25:31,026
CODEX ANALYSIS TO IDENTIFY IPT

643
00:25:31,026 --> 00:25:31,660
GREATERUNE CELL SUBSETS

644
00:25:31,660 --> 00:25:32,427
THROUGHOUT THE LIVER.

645
00:25:32,427 --> 00:25:34,563
THE WAY WE DO THIS IS BASICALLY,

646
00:25:34,563 --> 00:25:36,865
YOU KNOW WE DIVIDE THE CELLS

647
00:25:36,865 --> 00:25:39,067
INTO CD45 POSITIVE IMMUNE CELLS

648
00:25:39,067 --> 00:25:40,569
AND PAREN CHIMAL CELLS.

649
00:25:40,569 --> 00:25:44,840
WE LOOK AT DIFFERENT NOT P A

650
00:25:44,840 --> 00:25:52,214
RACHYMALL CELLS, THE MARKERS,

651
00:25:52,214 --> 00:25:53,582
HEPATOCYTES, ENDOTHELIAL CELLS

652
00:25:53,582 --> 00:25:59,087
AND  VASC VASCULAR ENDOTHELIAL

653
00:25:59,087 --> 00:26:00,756
CELLS, AND WE LOOK AT THE CELLS

654
00:26:00,756 --> 00:26:01,923
ON TOP OF THE LIVER EMPLOY WE

655
00:26:01,923 --> 00:26:04,393
SELECTED A GROUP OF MARKERS THAT

656
00:26:04,393 --> 00:26:05,961
CAN HELP US ASSESS THE FUNCTION

657
00:26:05,961 --> 00:26:07,396
OF THE DIFFERENT IMMUNE CELLS

658
00:26:07,396 --> 00:26:13,034
EMPLOY SO WITH ALL THIS DATA,

659
00:26:13,034 --> 00:26:14,736
YOU GET YOU GET A LOT OF

660
00:26:14,736 --> 00:26:15,370
INFORMATION BUT BEFORE WE GO

661
00:26:15,370 --> 00:26:17,639
THERE I WILL LIKE TO SHARE THE

662
00:26:17,639 --> 00:26:18,340
PRIMARY IMAGES ACTUALLY THAT WE

663
00:26:18,340 --> 00:26:24,413
WERE ABLE TO OBLIGATIONS STAIN.

664
00:26:24,413 --> 00:26:26,047
SO THIS IS AN EXAMPLE OF THIS,

665
00:26:26,047 --> 00:26:27,549
YOU CAN SEE ON THE SLIDE.

666
00:26:27,549 --> 00:26:28,850
ON THE BOTTOM RIGHT IT IS

667
00:26:28,850 --> 00:26:30,786
BASICALLY THE TUMOR CORE, IN

668
00:26:30,786 --> 00:26:33,155
YELLOW, CAN YOU SEE RIM OF THIS

669
00:26:33,155 --> 00:26:42,764
TUMOR AND IN RED THE AREA OF THE

670
00:26:42,764 --> 00:26:43,832
NONTUMOR TISSUE AND SINCE THIS

671
00:26:43,832 --> 00:26:45,700
IS A MICROSCOPIC PICTURE, YOU

672
00:26:45,700 --> 00:26:47,669
CAN ZOOM IN AND SEE THE

673
00:26:47,669 --> 00:26:50,071
PERIPORTAL AREA AND RECOGNIZE

674
00:26:50,071 --> 00:26:51,373
THE DIFFERENT STRUCTURES THAT

675
00:26:51,373 --> 00:26:55,010
YOU FIND IN THE NONTUMOR LIVER.

676
00:26:55,010 --> 00:26:56,545
NOW, OBVIOUSLY, WE HAVE WAY TOO

677
00:26:56,545 --> 00:26:58,079
MANY MARKERS AS YOU CAN SEE ON

678
00:26:58,079 --> 00:27:00,248
THE SIDE THAT I CAN SHOW YOU ON

679
00:27:00,248 --> 00:27:02,884
1 PICTURE, SO LET ME SHOW YOU

680
00:27:02,884 --> 00:27:04,553
HOW THIS LOOKS ACTUALLY IN

681
00:27:04,553 --> 00:27:06,154
REALITY, SO THESE ARE THE

682
00:27:06,154 --> 00:27:08,223
DIFFERENT MARKERS THAT WE USED

683
00:27:08,223 --> 00:27:08,423
HERE.

684
00:27:08,423 --> 00:27:10,692
YOU CAN SEE IF WE TART JUST

685
00:27:10,692 --> 00:27:12,027
BASICALLY TURN THE LIGHT ON TO

686
00:27:12,027 --> 00:27:14,229
LOOK FOR KRRK DECKER 45 POSITIVE

687
00:27:14,229 --> 00:27:19,868
CELLS, OR IF WE LOOK FOR LIVER

688
00:27:19,868 --> 00:27:21,503
SIGNUE SOID CELLS, IF WE LOOK

689
00:27:21,503 --> 00:27:22,137
FOR MACROPHAGES THROUGHOUT THE

690
00:27:22,137 --> 00:27:23,872
LIVER, IF YOU ARE INTERESTED IN

691
00:27:23,872 --> 00:27:26,141
THE T-CELLS, YOU CAN FIND THEM,

692
00:27:26,141 --> 00:27:27,876
THE GRANUE LO SIGHTS OR FOR

693
00:27:27,876 --> 00:27:30,045
INITANCE IF YOU WANT TO TODAY

694
00:27:30,045 --> 00:27:31,580
B-CELLS YOU CAN SEE WHERE

695
00:27:31,580 --> 00:27:32,280
THEY'RE LOCATED.

696
00:27:32,280 --> 00:27:34,249
NOW ONCE YOU HAVE THIS DATA

697
00:27:34,249 --> 00:27:35,150
TRUSTEES THESE PATIENTS,

698
00:27:35,150 --> 00:27:40,522
OBVIOUSLY THERE IS A LOT OF WORK

699
00:27:40,522 --> 00:27:41,423
DOWN STREAM, SO SO AFTER

700
00:27:41,423 --> 00:27:43,358
STAINING THIS AND GET

701
00:27:43,358 --> 00:27:44,159
THANKSGIVING ON THE MICROSCOPE,

702
00:27:44,159 --> 00:27:46,161
YOU HAVE TO PERFORM TISSUE

703
00:27:46,161 --> 00:27:47,128
ANNOTATION SO YOU HAVE TO

704
00:27:47,128 --> 00:27:51,466
DETERMINE WHICH AREA OF THE

705
00:27:51,466 --> 00:27:52,634
SLIDE IS TUMORRED AND HERE I

706
00:27:52,634 --> 00:27:54,236
WOULD LIKE TO ACKNOWLEDGE THE

707
00:27:54,236 --> 00:27:56,137
WORK FROM DAVID CLIENER WHO

708
00:27:56,137 --> 00:28:06,481
HELPED US WITH THIS.

709
00:28:15,957 --> 00:28:17,726
THIS IS JUST ANOTHER EXAMPLE TO

710
00:28:17,726 --> 00:28:18,827
SHOW YOU FROM ANOTHER TISSUE TO

711
00:28:18,827 --> 00:28:20,529
SEE YOU HAD THIS LOOKS LIKE

712
00:28:20,529 --> 00:28:22,464
EMPLOY NOW HERE YOU SEE, SIMILAR

713
00:28:22,464 --> 00:28:27,836
TO SINGLE CELL DATA WE CAN THEN

714
00:28:27,836 --> 00:28:30,171
PERFORM IMMUNE ANALYSIS AND AND

715
00:28:30,171 --> 00:28:30,839
CHARACTERIZE THE'MUNE CELL

716
00:28:30,839 --> 00:28:32,140
SUBSETS ON THE HEAT MAP EMPLOY

717
00:28:32,140 --> 00:28:34,576
THE INTERESTING PART AGAIN, IS

718
00:28:34,576 --> 00:28:36,444
THE PART AFTERWARDS WHERE YOU

719
00:28:36,444 --> 00:28:38,046
ACTUALLY PERFORMED THE

720
00:28:38,046 --> 00:28:39,614
NEIGHBORHOOD ANALYSIS AND IN

721
00:28:39,614 --> 00:28:44,986
THIS CASE I HAVE TO GIVE A BIG

722
00:28:44,986 --> 00:28:48,056
COLLABORATORS THAT WE HAVE THAT

723
00:28:48,056 --> 00:28:49,858
DEVELOPED--NOT NOVEL BUT

724
00:28:49,858 --> 00:28:54,329
PROTOCOL OR CODE TO PERFORM THIS

725
00:28:54,329 --> 00:28:55,597
NEURAL NETWORK ANALYSIS WHICH IN

726
00:28:55,597 --> 00:28:57,499
THE END TOLD US THAT IF WE TRY

727
00:28:57,499 --> 00:28:59,200
TO FIND OUT WHICH IS THE MOST

728
00:28:59,200 --> 00:29:02,337
LIKELY CELL THAT IS CLOSE TO A

729
00:29:02,337 --> 00:29:08,877
MAIT, IT TURNED OUT TO BE A PDL1

730
00:29:08,877 --> 00:29:09,411
POSITIVE TUMOR ASSOCIATED

731
00:29:09,411 --> 00:29:09,711
MACROPHAGE.

732
00:29:09,711 --> 00:29:10,679
NOW THIS IS BASED ON COMPUTER

733
00:29:10,679 --> 00:29:12,147
ALGORITHM IN THE DATA WE FED

734
00:29:12,147 --> 00:29:13,715
INTO THE SYSTEM BUT BECAUSE WE

735
00:29:13,715 --> 00:29:15,350
HAVE IMAGES WE CAN ACTUALLY GO

736
00:29:15,350 --> 00:29:18,687
BACK AND SEE, IS THIS TRUE IN

737
00:29:18,687 --> 00:29:22,290
AND INDEED WE FIND THE MAITs

738
00:29:22,290 --> 00:29:26,461
NEXT TO THE CDL1 OR 6 POSITIVE

739
00:29:26,461 --> 00:29:27,028
MACROPHAGE.

740
00:29:27,028 --> 00:29:29,264
SO THIS IS AN IMMUNE CELLAT

741
00:29:29,264 --> 00:29:31,700
LAS PINTAS, I FOCUSED ON THE

742
00:29:31,700 --> 00:29:33,902
MAITs AND THEY ARE CLOSE

743
00:29:33,902 --> 00:29:34,869
PROXIMITY TO THE MA ROUGH ATOM

744
00:29:34,869 --> 00:29:37,072
PHAGES IN THE TUMOR SURROUNDING

745
00:29:37,072 --> 00:29:37,839
TISSUE.

746
00:29:37,839 --> 00:29:40,742
BUT THIS IS STILL DESCRIPTIVE.

747
00:29:40,742 --> 00:29:41,943
WE HAVE A LOT OF DATA, I DIDN'T

748
00:29:41,943 --> 00:29:43,745
SHOW YOU ALL THE SEQUENCING DATA

749
00:29:43,745 --> 00:29:52,621
WE HAVE BUT WE STILL DON'T KNOW

750
00:29:52,621 --> 00:29:54,322
BUT WE DON'T KNOW IF THIS IS

751
00:29:54,322 --> 00:29:55,690
REALLY FUNCTIONAL.

752
00:29:55,690 --> 00:29:56,958
SO WE DECIDED THAT FUNCTIONAL

753
00:29:56,958 --> 00:30:00,028
STUDIES ARE REQUIRED TO REALLY

754
00:30:00,028 --> 00:30:00,795
UNDERSTAND THE BIOLOGICAL

755
00:30:00,795 --> 00:30:03,465
SIGNIFICANCE OF THIS INTERACTION

756
00:30:03,465 --> 00:30:08,203
OF MAITs AND PDL1 POSITIVE

757
00:30:08,203 --> 00:30:15,410
TEMs, SO HOW DID WE DO THIS?

758
00:30:15,410 --> 00:30:16,611
WE ACTUALLY DID AND I WILL NOT

759
00:30:16,611 --> 00:30:20,315
SHOW YOU ALL OF THIS BUT WE TOOK

760
00:30:20,315 --> 00:30:22,350
6 DIFFERENT APPROACHES, SO WE

761
00:30:22,350 --> 00:30:24,252
PERFORMED STUDIES USING HUMAN

762
00:30:24,252 --> 00:30:26,121
DERIVED SAMPLES WHERE WE CAN

763
00:30:26,121 --> 00:30:27,055
ACTUALLY CO INCUBATE THEM XI

764
00:30:27,055 --> 00:30:28,023
WILL SHOW YOU THIS.

765
00:30:28,023 --> 00:30:30,792
I HAD ALREADY SHOWN YOU THAT WE

766
00:30:30,792 --> 00:30:32,293
HAVE MOUSE MODELS WE CAN USE

767
00:30:32,293 --> 00:30:35,330
THAT WE CAN LOOK AT USED TO

768
00:30:35,330 --> 00:30:37,032
STUDY MAITs, SO WE PERFORMED

769
00:30:37,032 --> 00:30:42,971
IN VIVO STUDIES WHERE WE BLOCK

770
00:30:42,971 --> 00:30:43,738
PDL1 INTERACTION.

771
00:30:43,738 --> 00:30:46,107
WE WENT BACK TO SINGLE CELL

772
00:30:46,107 --> 00:30:47,976
ANALYSIS FROM HUMAN AND TUMOR

773
00:30:47,976 --> 00:30:49,277
BEARING MICE.

774
00:30:49,277 --> 00:30:50,612
WE PERFORM DEPLETION TODAYS

775
00:30:50,612 --> 00:30:52,981
BECAUSE WE HAVE 2 CELLS THAT

776
00:30:52,981 --> 00:30:53,782
INTERACT WITH EACH OTHER, IT'S

777
00:30:53,782 --> 00:30:55,650
EASY TO TAKE 1 OUT AND SAY WHAT

778
00:30:55,650 --> 00:30:57,252
HAPPENS CAN WE SEE AN EFFECT?

779
00:30:57,252 --> 00:30:59,854
WE CAN BE EVEN MORE SPECIFIC AND

780
00:30:59,854 --> 00:31:01,656
USE CONDITIONAL KNOCKOUT MICE

781
00:31:01,656 --> 00:31:05,093
WHERE THE PDL1 IS SPECIFICALLY

782
00:31:05,093 --> 00:31:06,027
ELIMINATED ON MACROPHAGE SUBSETS

783
00:31:06,027 --> 00:31:07,796
AND WE HAD LIMITED DATA

784
00:31:07,796 --> 00:31:10,465
AVAILABLE FROM OUR OWN PATIENTS.

785
00:31:10,465 --> 00:31:13,668
TREATED WITH CHECK POINT

786
00:31:13,668 --> 00:31:14,736
INHIBITORS WITH ANTIPDL1 TO SEE

787
00:31:14,736 --> 00:31:16,471
WHETHER WE SEE AN EFFECT SIMILAR

788
00:31:16,471 --> 00:31:18,173
TO WHAT WE WOULD PREDICT

789
00:31:18,173 --> 00:31:19,174
PRACTICES OUR MOUSE STUDIES AS

790
00:31:19,174 --> 00:31:24,846
WELL AS HUMAN STUDIES.

791
00:31:24,846 --> 00:31:27,115
SO LET'S START WITH THE FIRST 1,

792
00:31:27,115 --> 00:31:29,317
WE TOOK TISSUE FROM SPECIMEN,

793
00:31:29,317 --> 00:31:32,487
PRIMARY PATIENTS WITH HCC, AND

794
00:31:32,487 --> 00:31:34,422
WE ISOLATED MONONUCLEAR CELLS

795
00:31:34,422 --> 00:31:38,526
AND ISOLATED THEM TO

796
00:31:38,526 --> 00:31:40,495
TETRAMERPOSITIVE MAITs AS WELL

797
00:31:40,495 --> 00:31:41,996
AS TUMOR ASSOCIATED MA ROUGH

798
00:31:41,996 --> 00:31:45,400
ATOM PHAGES AND WE COLOR THEM

799
00:31:45,400 --> 00:31:50,038
AND THE RESULTS ARE SHOWN HERE.

800
00:31:50,038 --> 00:31:52,207
IF WE COCULTURE THE SALES, THEY

801
00:31:52,207 --> 00:31:54,476
ARE INNATE THIS THEIR 80 TO

802
00:31:54,476 --> 00:31:55,410
PRODUCE INTERFERON-GAMMA, AS YOU

803
00:31:55,410 --> 00:31:59,814
SEE ON THE LEFT, THE CONTROL IS

804
00:31:59,814 --> 00:32:01,149
GOING DOWN AND THEY HAVE NO

805
00:32:01,149 --> 00:32:02,617
EFFECT EMPLOY THIS IS INDEED

806
00:32:02,617 --> 00:32:03,051
CONTACT DEPENDENT.

807
00:32:03,051 --> 00:32:04,886
IF WE PUT THE SAME EXPERIMENT IN

808
00:32:04,886 --> 00:32:06,321
A TRANSFER WHERE WE PUT A

809
00:32:06,321 --> 00:32:07,822
MEMBRANE BETWEEN THE CELLS, WE

810
00:32:07,822 --> 00:32:09,724
DON'T SEE THE EFFECT ANYMORE, WE

811
00:32:09,724 --> 00:32:10,692
SEE INTERFERON-GAMMA IS GOING

812
00:32:10,692 --> 00:32:12,827
UP, AND THE SAME APPLIES TO AN

813
00:32:12,827 --> 00:32:14,696
EXPERIMENTAL SETTING WHERE WE

814
00:32:14,696 --> 00:32:17,465
NOW USE AN ANTIBODY AGAINST PDL1

815
00:32:17,465 --> 00:32:18,767
SO THAT THIS INTERACTION IS

816
00:32:18,767 --> 00:32:20,635
BLOCKED AND AGAIN THE FUNCTION

817
00:32:20,635 --> 00:32:22,537
OF THESE MAITs IS INKRESSED

818
00:32:22,537 --> 00:32:23,371
AND INTERFERON-GAMMA IS GOING

819
00:32:23,371 --> 00:32:24,172
UP.

820
00:32:24,172 --> 00:32:26,274
O THIS IS FIRST INDICATION THAT

821
00:32:26,274 --> 00:32:29,444
INDEED THIS INTERACTION MAY BE

822
00:32:29,444 --> 00:32:32,147
AT LEAST RELEVANT FOR THE

823
00:32:32,147 --> 00:32:33,448
DYSFUNCTION OF MARK ITs.

824
00:32:33,448 --> 00:32:37,452
HOW ABOUT AN IN VIVO EXPERIMENT?

825
00:32:37,452 --> 00:32:40,188
SO NEXT WE WENT AHEAD AND USED

826
00:32:40,188 --> 00:32:41,956
TUMOR MODEL THAT WE GENERATED

827
00:32:41,956 --> 00:32:42,957
WHERE WE INJECT TUMORS STRAIGHT

828
00:32:42,957 --> 00:32:46,728
INTO THE LIVER AND WE TREAT THEM

829
00:32:46,728 --> 00:32:47,128
WITH PDL1.

830
00:32:47,128 --> 00:32:48,730
AND INDEED IF WE DO THIS YOU CAN

831
00:32:48,730 --> 00:32:55,103
SEE ALL OF A SUDDEN MAITs

832
00:32:55,103 --> 00:32:56,938
INCREASE UPON PDL1 TREATMENT,

833
00:32:56,938 --> 00:33:01,276
IT'S NOT ONLY THAT MAITs GO UP

834
00:33:01,276 --> 00:33:03,912
BUT THE OTHERS GO UP AS WELL.

835
00:33:03,912 --> 00:33:09,450
SO FOR THOSE WHO ASKING ME WHY I

836
00:33:09,450 --> 00:33:11,553
USE THE MC38, I AM SHOWING YOU

837
00:33:11,553 --> 00:33:13,888
WHERE WE USE THESE TUMORS.

838
00:33:13,888 --> 00:33:15,623
THEN WE WENT AHEAD AND LOOKED AT

839
00:33:15,623 --> 00:33:18,526
MORE DETAIL AT THE HUMAN DATA

840
00:33:18,526 --> 00:33:21,162
THAT WE HAD AND MORE IMPORTANTLY

841
00:33:21,162 --> 00:33:31,406
AT THE MYELOID CELLS.

842
00:33:31,406 --> 00:33:31,940
I TOLD YOU THAT WE PERFORM

843
00:33:31,940 --> 00:33:32,540
SINGLE CELL ANALYSIS WHERE WE

844
00:33:32,540 --> 00:33:33,174
IDENTIFY THE DIFFERENT B-CELLS,

845
00:33:33,174 --> 00:33:33,808
T-CELLS AND THE MYELOID CLUSTER.

846
00:33:33,808 --> 00:33:34,442
WE ZOOMED INTO THE MYELOID CLUOF

847
00:33:34,442 --> 00:33:35,043
THENER MORE DETAIL AND FOUND

848
00:33:35,043 --> 00:33:35,677
THERE WERE ACTUALLY 6 DIFFERENT

849
00:33:35,677 --> 00:33:38,613
CLUSTERS THAT WE COULD IESHES

850
00:33:38,613 --> 00:33:39,147
DENTIFY.

851
00:33:39,147 --> 00:33:44,652
ONE OF THESE CLUSTERS, WAS

852
00:33:44,652 --> 00:33:46,821
ENRICHED IN CD163, THAT'S THE

853
00:33:46,821 --> 00:33:47,455
SECOND CLUSTER.

854
00:33:47,455 --> 00:33:50,258
THESE ARE THE TUMOR ASSOCIATED

855
00:33:50,258 --> 00:33:55,330
MACROFAINLS WHICH ALSO EXPRESS

856
00:33:55,330 --> 00:33:55,530
206.

857
00:33:55,530 --> 00:33:57,031
WE LOOK AT THESE CELLS IN MORE

858
00:33:57,031 --> 00:33:58,199
DETAIL AND WHAT WE WERE ABLE TO

859
00:33:58,199 --> 00:34:04,806
SEE IS THAT IF WE LOOK FOR THE

860
00:34:04,806 --> 00:34:05,640
CD163 CDLB MACROPHAGES WE FIND

861
00:34:05,640 --> 00:34:07,775
THEM IN THE TUMOR TO BE

862
00:34:07,775 --> 00:34:08,676
INCREASED IF WE COLLECT SASM

863
00:34:08,676 --> 00:34:10,979
ETCHS FROM PATIENTS WHO HAVE

864
00:34:10,979 --> 00:34:12,013
HCC, VERSUS THOSE PATIENTS THAT

865
00:34:12,013 --> 00:34:14,949
HAVE OTHER LIVER DISEASES BUT

866
00:34:14,949 --> 00:34:16,084
NOT A TUMOR.

867
00:34:16,084 --> 00:34:17,952
AND THIS INDICATES THAT THE

868
00:34:17,952 --> 00:34:20,688
PRESENCE OF A TUMOR ACTUALLY

869
00:34:20,688 --> 00:34:22,423
SIGNALS TO THE ENVIRONMENT AND

870
00:34:22,423 --> 00:34:25,193
LEADS TO THIS ACCUMULATION OF

871
00:34:25,193 --> 00:34:28,830
TUMOR ASSOCIATED MACROPHAGES

872
00:34:28,830 --> 00:34:29,631
WHICH INEXPERT IMMUNOSUPPRESSIVE

873
00:34:29,631 --> 00:34:32,066
FUNCTION AND 1 OF THE MECHANISMS

874
00:34:32,066 --> 00:34:34,736
IS BY UPREGGULING THE PDL1 AND

875
00:34:34,736 --> 00:34:36,204
IT'S UPREGULATED ON THESE

876
00:34:36,204 --> 00:34:37,505
MACROPHAGES.

877
00:34:37,505 --> 00:34:39,307
NOW BASED ON THIS DATA, WHERE WE

878
00:34:39,307 --> 00:34:42,510
SHOWED THAT IT'S INDEED THE PDL1

879
00:34:42,510 --> 00:34:43,411
EXPRESSION ON THESE MACROPHAGES

880
00:34:43,411 --> 00:34:45,280
AND WHAT I AGAIN DOESN'T SHOW

881
00:34:45,280 --> 00:34:48,650
YOU THERE ARE CSFR POSITIVE

882
00:34:48,650 --> 00:34:50,084
MACROPHAGES, WE WENT TO THE NEXT

883
00:34:50,084 --> 00:34:54,656
STEP, AND CONDUCTED STUDIES IN

884
00:34:54,656 --> 00:34:56,391
MICE WHERE WE NOW SPECIFICALLY

885
00:34:56,391 --> 00:34:59,227
KNOCK OUT THE PDECKER L1 ON THE

886
00:34:59,227 --> 00:34:59,961
MOUSE MACROPHAGES AND YOU CAN

887
00:34:59,961 --> 00:35:04,065
SEE THIS WELLS TO AN INCREASE OF

888
00:35:04,065 --> 00:35:06,601
MAITs, AND AN INCREASE OF

889
00:35:06,601 --> 00:35:11,372
INTERFERON-GAMMA AS WELL AS

890
00:35:11,372 --> 00:35:12,707
INCREASE IN GRANZYME PRODUCTION,

891
00:35:12,707 --> 00:35:14,409
THIS IS ALSO SHOWN ON THE KNOCK

892
00:35:14,409 --> 00:35:15,944
OUT ON THE DENDRITIC CELLS BUT

893
00:35:15,944 --> 00:35:17,812
HERE WE DON'T SEE THE SAME

894
00:35:17,812 --> 00:35:26,854
EFFECTS ON THE CSFR+ TAMs.

895
00:35:26,854 --> 00:35:28,823
LAST BUT NOT LEAST, WE WERE

896
00:35:28,823 --> 00:35:32,460
ASKING CAN WE USE THESE MAITs

897
00:35:32,460 --> 00:35:35,363
TO ACTIVATE IMMUNE RESPONSE IN

898
00:35:35,363 --> 00:35:37,899
COMBINATION OF PDL1 THERAPY.

899
00:35:37,899 --> 00:35:39,534
IMEAN WE USED AN ANIMAL MODEL,

900
00:35:39,534 --> 00:35:42,437
AND WE INYECT THE TUMOR CELL AT

901
00:35:42,437 --> 00:35:44,305
55.1 WHICH IS AN HKRRK C CELL,

902
00:35:44,305 --> 00:35:46,841
IN A WILD-TYPE MOUSE OR DOESN'T

903
00:35:46,841 --> 00:35:50,578
HAVE ANY MAITs, AN MR1 KNOCK

904
00:35:50,578 --> 00:35:57,685
OUT MOUSE, WE USE 5 PRU AND CPG

905
00:35:57,685 --> 00:35:58,619
WHICH ACTIVATES MAITS AND WHAT

906
00:35:58,619 --> 00:36:01,055
YOU CAN SEE IN THE MIDDLE GRAPH

907
00:36:01,055 --> 00:36:02,757
AND THE WILD-TYPE MICE AND WHILE

908
00:36:02,757 --> 00:36:05,059
WE DON'T FIND AN EFFECT IN THIS

909
00:36:05,059 --> 00:36:07,261
PARTICULAR MODEL USING ANTIPDL1

910
00:36:07,261 --> 00:36:09,597
EITHER AS A SINGLE AGENT OR TO

911
00:36:09,597 --> 00:36:12,066
ACTIVATE T-CELLS OR THE 5 OF PRU

912
00:36:12,066 --> 00:36:15,603
AND CPG, TO ACTIVATE THE

913
00:36:15,603 --> 00:36:16,671
MAITs, AND THE COMBINATION

914
00:36:16,671 --> 00:36:18,406
INDEED IS LEADING TO A REDUCTION

915
00:36:18,406 --> 00:36:21,809
OF TUMOR WEIGHT OR TUMOR GROWTH.

916
00:36:21,809 --> 00:36:24,278
CAN THIS MECHANISM IS INDEED

917
00:36:24,278 --> 00:36:26,414
DEPENDENT ON MAITs, BECAUSE IF

918
00:36:26,414 --> 00:36:28,916
YOU USE AN MR1 KNOCK OUT MOUSE,

919
00:36:28,916 --> 00:36:33,254
THERE IS BASICALLY NO EEIVET

920
00:36:33,254 --> 00:36:33,454
LEFT.

921
00:36:33,454 --> 00:36:36,424
SO I BELIEVE WHAT I WAS ABLE TO

922
00:36:36,424 --> 00:36:38,159
HOPE--YOU KNOW WHAT I WAS ABLE

923
00:36:38,159 --> 00:36:40,995
TO SHOW YOU HERE IS THAT THESE

924
00:36:40,995 --> 00:36:45,400
CELLS WHICH ARE VERY ABUNDANT

925
00:36:45,400 --> 00:36:47,869
ABOUT AT THE SAME FREQUENCY THAN

926
00:36:47,869 --> 00:36:50,505
CD8 T-CELLS IN THE LIVER, THEY

927
00:36:50,505 --> 00:36:53,174
CAN ACTUALLY EXERT VERY POTENT

928
00:36:53,174 --> 00:36:55,009
ANTITUMOR IMMUNITY.

929
00:36:55,009 --> 00:36:57,278
THEY ARE COMPROMISED IN THE

930
00:36:57,278 --> 00:36:58,479
CONTEXT OF A TUMOR AND THE

931
00:36:58,479 --> 00:37:00,915
MECHANISM THAT WE PROPOSE IS

932
00:37:00,915 --> 00:37:02,817
BEASKLY SHOWN HERE.

933
00:37:02,817 --> 00:37:04,052
SO WE BELIEVE THAT WHEN THE

934
00:37:04,052 --> 00:37:07,522
CELLS ARE IN THE ADJACENT LIVER,

935
00:37:07,522 --> 00:37:10,758
THEY INTERACT WITH CD163

936
00:37:10,758 --> 00:37:14,028
POSITIVE TUMOR ASSOCIATED

937
00:37:14,028 --> 00:37:15,463
MACROPHAGES THROUGH PD1, PDL1.

938
00:37:15,463 --> 00:37:18,499
THIS LEADS TO A DECREASE IN THE

939
00:37:18,499 --> 00:37:20,334
INFILTRATION IN THE TUMOR CORE

940
00:37:20,334 --> 00:37:21,869
AND A DECREASE OF THEIR FUNCTION

941
00:37:21,869 --> 00:37:23,271
EMPLOY THEY BECOME

942
00:37:23,271 --> 00:37:23,604
DYSFUNCTIONAL.

943
00:37:23,604 --> 00:37:25,139
I'VE SHOWN YOU SOME OF THE READ

944
00:37:25,139 --> 00:37:27,742
OUTS, I'VE SHOWN YOU A DECREASE

945
00:37:27,742 --> 00:37:31,379
IN INTERFERON-GAMMA, A DECREASE

946
00:37:31,379 --> 00:37:35,450
OF GRANZYME B, I DID NOT SHOW

947
00:37:35,450 --> 00:37:36,717
TNF ALPHA BUT WE DID LOOK AT IT,

948
00:37:36,717 --> 00:37:38,719
I DIDN'T SHOW IT.

949
00:37:38,719 --> 00:37:40,321
I'VE SHOWN YOU CONDITIONAL KNOCK

950
00:37:40,321 --> 00:37:41,956
OUT IS ITS, I'VE SHOWN YOU

951
00:37:41,956 --> 00:37:46,060
STUDIES WHEREY WOO BLOCK PDL1,

952
00:37:46,060 --> 00:37:47,261
USING ANTIABOUTS, I DIDN'T SHOW

953
00:37:47,261 --> 00:37:49,931
THE DATA WHERE WE BLOCK CSFR,

954
00:37:49,931 --> 00:37:51,666
BUT IT'S A SIMILAR MECHANISM

955
00:37:51,666 --> 00:37:54,735
WHERE WE DEPLETE THESE

956
00:37:54,735 --> 00:37:56,804
MACROFEAJS USING OTHER MODELS WE

957
00:37:56,804 --> 00:37:58,639
HAVE AVAILABLE, THIS LEADS TO AN

958
00:37:58,639 --> 00:38:00,908
INCREASE OF THE FUNCTION,

959
00:38:00,908 --> 00:38:04,078
INCREASE IN INTERFERON-GAMMA,

960
00:38:04,078 --> 00:38:06,247
GRANZYME, AND THE TUMOR, AND THE

961
00:38:06,247 --> 00:38:08,316
TUMOR BECOMES ENFIL TRAITED BY

962
00:38:08,316 --> 00:38:12,019
MAITs AND BECOMES MORE

963
00:38:12,019 --> 00:38:18,259
INFLAMED AND ULTIMATELY SHRINKS

964
00:38:18,259 --> 00:38:21,929
IN TUMOR SIZE EMPLOY NOW WHAT I

965
00:38:21,929 --> 00:38:24,232
HAVE AS A TITLE IN MY TALK WAS

966
00:38:24,232 --> 00:38:27,502
FROM BENCH TO BEDSIDE AND BACK

967
00:38:27,502 --> 00:38:27,869
AGAIN.

968
00:38:27,869 --> 00:38:30,404
AND I THINK WHAT I'M TRYING TO

969
00:38:30,404 --> 00:38:32,507
SHOW YOU IS, AND THAT'S REALLY

970
00:38:32,507 --> 00:38:34,075
THE THEME OF WHAT I AM TRYING TO

971
00:38:34,075 --> 00:38:36,144
DO AS THE THEME OF THIS TALK IS

972
00:38:36,144 --> 00:38:38,779
TO SHOW YOU HOW CAN WE COMBOYNE

973
00:38:38,779 --> 00:38:41,115
HUMAN DATA AND MOUSE DATA TO GET

974
00:38:41,115 --> 00:38:42,517
REALLY THE MAXIMUM INFORMATION

975
00:38:42,517 --> 00:38:42,984
OUT OF IT.

976
00:38:42,984 --> 00:38:48,723
AND WHAT I WOULD LIKE IN THE

977
00:38:48,723 --> 00:38:49,924
LAST 10 MINUTES OR LESS TO

978
00:38:49,924 --> 00:38:54,328
ACTUALLY SHARE WITH YOU SOME

979
00:38:54,328 --> 00:38:55,096
UNPUBLISHED DATA.

980
00:38:55,096 --> 00:38:56,297
THIS IS ALTHOUGH IT'S RECENTLY

981
00:38:56,297 --> 00:38:58,432
PUBLISHED DAILY BASIS THEA ISSUE

982
00:38:58,432 --> 00:39:00,234
UNPUBLISHED DATA WHERE

983
00:39:00,234 --> 00:39:03,671
NONAPOPTOTIC I FEEL REALLY PUSH

984
00:39:03,671 --> 00:39:08,342
THIS TO THE EXTREME AND IT'S

985
00:39:08,342 --> 00:39:09,277
OBVIOUSLY VERY PROVOCATIVE, THE

986
00:39:09,277 --> 00:39:10,912
DATA I SHOW YOU IS NOT COMPLETE

987
00:39:10,912 --> 00:39:11,913
AND I THINK IT'S VERY

988
00:39:11,913 --> 00:39:14,649
INTERESTING AND AGAIN, YOU KNOWS

989
00:39:14,649 --> 00:39:16,817
THIS QUESTION, YOU KNOW HOW CAN

990
00:39:16,817 --> 00:39:18,853
YOU USE HUMAN DATA OR MOUSE DATA

991
00:39:18,853 --> 00:39:26,494
TO GET THE MOST BEING ABOUT IT.

992
00:39:26,494 --> 00:39:31,098
SO RIGHT NOW THIS IS ONGOING IN

993
00:39:31,098 --> 00:39:33,467
THE CLINICAL CENTER AND I WILL

994
00:39:33,467 --> 00:39:35,503
PUT MY HEAD ON AS A MEDICAL

995
00:39:35,503 --> 00:39:35,803
ONCOLOGIST.

996
00:39:35,803 --> 00:39:42,577
SO AS A MEDICAL ONCOLOGIST, WE

997
00:39:42,577 --> 00:39:48,683
USED ANTICDLA4, AND ANTIPDL1,

998
00:39:48,683 --> 00:39:50,184
AND COLLEAGUES THAT USUALLY

999
00:39:50,184 --> 00:39:51,485
WORKS THEY HAVE 1 DRUG THAT

1000
00:39:51,485 --> 00:39:53,120
WORKS, THEY HAVE A SECOND DRUG

1001
00:39:53,120 --> 00:39:54,855
WORKS AND THEN THEY ASK THE

1002
00:39:54,855 --> 00:39:56,357
SCIENTIFIC QUESTION, WHAT HAPPEN

1003
00:39:56,357 --> 00:39:57,325
FIST YOU COMBINE THEM?

1004
00:39:57,325 --> 00:39:58,960
SO I DID THE SAME THING.

1005
00:39:58,960 --> 00:40:01,262
I USED ALL THE DRUGS HERE, WE

1006
00:40:01,262 --> 00:40:05,600
PERFOR THE PURPOSED READ OUTS

1007
00:40:05,600 --> 00:40:08,369
AND BIOPSIES, BLOOD SAMPLES,

1008
00:40:08,369 --> 00:40:09,704
LOOKED AT TAIJING, ET CETERA.

1009
00:40:09,704 --> 00:40:11,172
AND TOLD YOU WE HAD DONE STUDIES

1010
00:40:11,172 --> 00:40:14,041
BEFORE WHERE WE ONLY USED THE

1011
00:40:14,041 --> 00:40:16,978
SAME COMBINATION BUT NO

1012
00:40:16,978 --> 00:40:18,279
ANTIVEGFOR OR THE SAME

1013
00:40:18,279 --> 00:40:20,248
COMBINATION WHERE WE DIDN'T HAVE

1014
00:40:20,248 --> 00:40:21,082
ANTIPUNISHING DL1.

1015
00:40:21,082 --> 00:40:24,585
OKAY, SO THIS IS SUPER EXCITING.

1016
00:40:24,585 --> 00:40:27,288
BUT I SEE THIS WE ONLY TREATED 7

1017
00:40:27,288 --> 00:40:30,358
PATIENTS, AND YOU CAN SEE THE

1018
00:40:30,358 --> 00:40:31,125
OUTCOME AND THIS AGAIN SOMETHING

1019
00:40:31,125 --> 00:40:33,961
YOU HAVE TO TAKE WITH A GRAIN OF

1020
00:40:33,961 --> 00:40:35,463
SALT BECAUSE WE CANNOT COMPARE

1021
00:40:35,463 --> 00:40:37,465
BETWEEN TRIALS AND THERE ARE

1022
00:40:37,465 --> 00:40:38,132
DIFFERENCE IN DOSING, ET CETERA,

1023
00:40:38,132 --> 00:40:41,702
SO YOU KNOW THIS IS ALL-I TAKE

1024
00:40:41,702 --> 00:40:43,537
ALL THOSE CRITICISM AND THESE

1025
00:40:43,537 --> 00:40:44,705
ARE VERY SMALL PATIENT NUMBERS,

1026
00:40:44,705 --> 00:40:48,075
BUT THE DATA IS QUITE

1027
00:40:48,075 --> 00:40:48,376
SURPRISING.

1028
00:40:48,376 --> 00:40:53,447
YOU CAN SEE THAT ONCE WE USE THE

1029
00:40:53,447 --> 00:40:55,816
[INDISCERNIBLE] IN RED, ON THE

1030
00:40:55,816 --> 00:41:00,021
BOTTOM YOU SEE THE PROGRESS FREE

1031
00:41:00,021 --> 00:41:01,122
SURVIVAL, IT'S SIGNIFICANTLY

1032
00:41:01,122 --> 00:41:02,657
LONGER THAN BEFORE, BELIEVE ME,

1033
00:41:02,657 --> 00:41:05,459
THE PATIENTS WE SEE HERE HAVEN'T

1034
00:41:05,459 --> 00:41:07,028
CHANGED MUCH IN THE PAST 6 OR

1035
00:41:07,028 --> 00:41:10,164
8IERS AND THIS ALSO LEADS TO A

1036
00:41:10,164 --> 00:41:11,098
DIFFERENCE IN SURVIVAL AS CAN

1037
00:41:11,098 --> 00:41:13,768
YOU SEE ON TOP WITH JUST A VERY

1038
00:41:13,768 --> 00:41:14,201
FEW PATIENTS.

1039
00:41:14,201 --> 00:41:16,003
NOW IF IT WAS ONLY THIS, I WOULD

1040
00:41:16,003 --> 00:41:17,538
NOT BE VERY EXCITED BECAUSE I

1041
00:41:17,538 --> 00:41:19,240
WOULD SAY IT'S PROBABLY PATIENT

1042
00:41:19,240 --> 00:41:21,342
SELECTION EMPLOY YOU KNOW, 7

1043
00:41:21,342 --> 00:41:25,179
PATIENTS, IT'S REALLY NOTHING,

1044
00:41:25,179 --> 00:41:26,314
BUT THERE'S MORE.

1045
00:41:26,314 --> 00:41:28,949
THESE PEASHTS DEVELOP

1046
00:41:28,949 --> 00:41:29,917
SIGNIFICANT IMMUNE RELATED

1047
00:41:29,917 --> 00:41:30,284
ADVERSE EVENTS.

1048
00:41:30,284 --> 00:41:31,952
SO CAN YOU SEE HERE ON THE

1049
00:41:31,952 --> 00:41:34,155
RIGHT, THE 7 PATIENTS.

1050
00:41:34,155 --> 00:41:37,091
YOU CAN SEE THE DAY WHEN THESE

1051
00:41:37,091 --> 00:41:37,892
IMMUNE RELATED ADVERSE EVENTS

1052
00:41:37,892 --> 00:41:40,561
OCCURRED IS YOU CAN SEE THE

1053
00:41:40,561 --> 00:41:40,895
GRADE.

1054
00:41:40,895 --> 00:41:44,065
AND I WILL LIKE TO POINT YOUR

1055
00:41:44,065 --> 00:41:45,132
ATTENTION TO THE ADVERSE EVENTS

1056
00:41:45,132 --> 00:41:49,103
THAT TARTS WITH AN M.

1057
00:41:49,103 --> 00:41:53,841
SUCH AS MYOCYTEIS, MYASTHENIA,

1058
00:41:53,841 --> 00:41:56,711
MY O CARDITEIS, ATRIAL

1059
00:41:56,711 --> 00:41:57,745
FIBRILLATION, THESE ARE NOT THE

1060
00:41:57,745 --> 00:42:00,448
TYPES OF EVENTS WE USUALLY FIND

1061
00:42:00,448 --> 00:42:01,082
IN OUR PATIENTS.

1062
00:42:01,082 --> 00:42:02,316
AND I KNOW THIS' A LOT OF LAB

1063
00:42:02,316 --> 00:42:04,285
PEOPLE IN HERE SO I THOUGHT I

1064
00:42:04,285 --> 00:42:06,520
WOULD GO DEEPER AND SHOW YOU A

1065
00:42:06,520 --> 00:42:09,657
SLIDE FROM 1 OF THE

1066
00:42:09,657 --> 00:42:11,992
PRESENTATIONS THAT I GOT FROM

1067
00:42:11,992 --> 00:42:13,894
OUR COLLEAGUES FROM NEUROLOGY

1068
00:42:13,894 --> 00:42:15,062
THAT DESCRIBED THE HOSPITAL

1069
00:42:15,062 --> 00:42:15,963
COURSE OF 1 OF THESE PEASHTS AND

1070
00:42:15,963 --> 00:42:20,301
I JUST HIGHLIGHT A FEW OF THESE 

1071
00:42:20,301 --> 00:42:27,174
YOU SEE INDUCED--NEW CHECK POINT

1072
00:42:27,174 --> 00:42:31,445
INHIBITOR--SO THESE ARE HEART

1073
00:42:31,445 --> 00:42:33,214
ENZYMES, YOU SEE MY O CARDITEIS,

1074
00:42:33,214 --> 00:42:36,350
YOU SEE WEAKNESS, THE PATIENT

1075
00:42:36,350 --> 00:42:39,653
WAS UNAWARE OF THE EXPENTINE

1076
00:42:39,653 --> 00:42:41,956
REGIMEN OF HIS SWALLOWING

1077
00:42:41,956 --> 00:42:43,824
IMPAIRMENT, EYE MOVEMENT GOT

1078
00:42:43,824 --> 00:42:46,127
BETTER, THE VOICE WAS SO HORSE

1079
00:42:46,127 --> 00:42:48,596
HE WAS NOW USING A VOICE

1080
00:42:48,596 --> 00:42:51,832
AMPLIFIER SO OUR PATIENT

1081
00:42:51,832 --> 00:42:52,800
COULDN'T REALLY SPEAK ANYMORE,

1082
00:42:52,800 --> 00:42:54,068
AND THE PRIMARY TEAM SO THAT'S

1083
00:42:54,068 --> 00:42:57,438
US, WE EVEN CONSIDERED A

1084
00:42:57,438 --> 00:42:58,506
PUNISHING EC FOR THAT PATIENT

1085
00:42:58,506 --> 00:42:59,707
ISSUES THAT'S FOR THE PEOPLE WHO

1086
00:42:59,707 --> 00:43:01,642
DON'T DO THE WORK AT THE TIME,

1087
00:43:01,642 --> 00:43:06,180
THEY PUT A TUBE INTO THE

1088
00:43:06,180 --> 00:43:06,447
PATIENT.

1089
00:43:06,447 --> 00:43:09,650
SO WE SEE SIGNIFICANT RELATED

1090
00:43:09,650 --> 00:43:10,818
ADVERSE EVENTS IN THESE

1091
00:43:10,818 --> 00:43:12,887
PATIENTS.

1092
00:43:12,887 --> 00:43:13,521
THIS CAUGHT OUR ATTENTION AND

1093
00:43:13,521 --> 00:43:15,356
I'M NOT GOING TO TELL YOU MORE

1094
00:43:15,356 --> 00:43:17,625
ABOUT THE CLINICAL PART BUT WHAT

1095
00:43:17,625 --> 00:43:19,193
I THINK--WHAT I THOUGHT AT THAT

1096
00:43:19,193 --> 00:43:21,796
POINT WAS, THERE MUST BE A VERY,

1097
00:43:21,796 --> 00:43:24,865
VERY STRONG IMMUNE RESPONSE.

1098
00:43:24,865 --> 00:43:27,802
SO THIS IS NOW THE--OUTLINE FOR

1099
00:43:27,802 --> 00:43:29,203
THE CORRELATIVE STUDIES FOR THIS

1100
00:43:29,203 --> 00:43:30,838
PROJECT AND DON'T WORRY, I WILL

1101
00:43:30,838 --> 00:43:32,606
NOT SHOW YOU ALL OF THIS BUT WE

1102
00:43:32,606 --> 00:43:35,176
HAD TUMOR BIOPSIES AND I WE

1103
00:43:35,176 --> 00:43:37,044
TRANSLATED ALL THIS INTO A

1104
00:43:37,044 --> 00:43:38,913
PHOSPHORYLATED MODEL TO VERIFY

1105
00:43:38,913 --> 00:43:39,747
AGAIN SIMILAR TO WHAT I'VE SHOWN

1106
00:43:39,747 --> 00:43:42,416
YOU BEFORE, YOU KNOW WHAT THE

1107
00:43:42,416 --> 00:43:43,484
UNDERLYING MECHANISM IS.

1108
00:43:43,484 --> 00:43:45,719
LET'S START ANALYZING THE

1109
00:43:45,719 --> 00:43:48,255
T-CELLS, WE SAW AS EXPECTED A

1110
00:43:48,255 --> 00:43:49,523
VERY STRONG KD8 T-CELL RESPONSE

1111
00:43:49,523 --> 00:43:51,859
APPROXIMATE WHEN I SAY DOUBLE

1112
00:43:51,859 --> 00:43:53,527
VERSUS TRIPLE ISSUE, WE

1113
00:43:53,527 --> 00:43:55,296
COLLECT--COMPARE SORRY, FROM THE

1114
00:43:55,296 --> 00:43:56,697
PASHTS THAT ONLY RECEIVE CTLA-4

1115
00:43:56,697 --> 00:43:59,800
AND PDL1 WITH THE 1S THAT

1116
00:43:59,800 --> 00:44:03,704
RECEIVE THE DOUBLET WITH THE

1117
00:44:03,704 --> 00:44:03,938
ANTIBGF.

1118
00:44:03,938 --> 00:44:05,606
BUT WHAT IS IT DOING?

1119
00:44:05,606 --> 00:44:07,808
WHAT IS CONSIDERED THE MOST

1120
00:44:07,808 --> 00:44:09,443
STRONG IMMUNE CHECK POINT

1121
00:44:09,443 --> 00:44:10,878
INHIBITOR, BUT APPARENTLY CD8

1122
00:44:10,878 --> 00:44:13,581
T-CELLS ARE WAY MORE ACTIVATED.

1123
00:44:13,581 --> 00:44:16,016
AND THEN QUITE SURPRISINGLY

1124
00:44:16,016 --> 00:44:18,686
THERE WAS AN INCREASE IN

1125
00:44:18,686 --> 00:44:20,754
REGULATORY T-CELLS.

1126
00:44:20,754 --> 00:44:22,389
WHY REGULATORY T-CELLS.

1127
00:44:22,389 --> 00:44:23,657
REGULATORY T-CELLS WOULD

1128
00:44:23,657 --> 00:44:25,025
SUPPRESS AN IMMUNE RESPONSE AND

1129
00:44:25,025 --> 00:44:25,993
I JUST TOLD YOU THESE PATIENT

1130
00:44:25,993 --> 00:44:28,529
HIS A GOOD OUTCOME AND THEY

1131
00:44:28,529 --> 00:44:30,164
DEVELOP CD8 IMMUNE RESPONSES AND

1132
00:44:30,164 --> 00:44:32,933
WE KNOW THESE REGULATORY T-CELLS

1133
00:44:32,933 --> 00:44:34,101
CAN REPRESS RESPONSES THROUGH A

1134
00:44:34,101 --> 00:44:35,469
DIFFERENT MECHANISM THROUGH

1135
00:44:35,469 --> 00:44:38,706
APCs AND SO WE KNOT REALLY

1136
00:44:38,706 --> 00:44:40,307
INTERESTED IN THIS.

1137
00:44:40,307 --> 00:44:41,408
THE OTHER FINDING WE MADE WAS

1138
00:44:41,408 --> 00:44:44,178
THE FOLLOWING.

1139
00:44:44,178 --> 00:44:48,048
WE HAD SERUM SAMPLES AND WE

1140
00:44:48,048 --> 00:44:50,484
COMPARE THEM WITH THE 1S THAT

1141
00:44:50,484 --> 00:44:52,119
HAVE THE TREATMENT, ASK WE SAW

1142
00:44:52,119 --> 00:44:55,823
THEY MADE A LOT OF IL12.

1143
00:44:55,823 --> 00:44:59,193
THIS IS THE FIRST COLUMN .

1144
00:44:59,193 --> 00:45:02,663
IF WE TREAT THESE PATIENTS WITH

1145
00:45:02,663 --> 00:45:05,232
ANTIBGF, SO WHAT IS THE

1146
00:45:05,232 --> 00:45:06,700
UNDERLYING MECHANISM?

1147
00:45:06,700 --> 00:45:09,069
SO WE WENT AHEAD AND TREATED OUR

1148
00:45:09,069 --> 00:45:10,037
MICE, WE TREATED THEM THE SAME

1149
00:45:10,037 --> 00:45:13,607
WAY, GAVE THEM THE COMBINATION,

1150
00:45:13,607 --> 00:45:16,310
AND INDEED WE WERE ABLE TO

1151
00:45:16,310 --> 00:45:16,877
REPEAT THIS.

1152
00:45:16,877 --> 00:45:18,312
WAWHAT WE HAD SEEN IN OUR

1153
00:45:18,312 --> 00:45:21,081
PATIENTS, WE SAW AN INCREASE OF

1154
00:45:21,081 --> 00:45:21,682
REGULATORY T-CELLS.

1155
00:45:21,682 --> 00:45:24,351
NOW WE WERE ABLE TO LOOK AT

1156
00:45:24,351 --> 00:45:27,121
THESE T-REGS IN MORE DETAIL, WE

1157
00:45:27,121 --> 00:45:31,625
SHOW THAT THEY MAKE A LOT OF

1158
00:45:31,625 --> 00:45:32,026
INTERFERON-GAMMA.

1159
00:45:32,026 --> 00:45:34,295
THEY TART TO UPREGULATE THE

1160
00:45:34,295 --> 00:45:36,931
TRANSCRIPTION FACTOR, AND THEY

1161
00:45:36,931 --> 00:45:38,332
DOWN REGULATE ANOTHER 1 HERE.

1162
00:45:38,332 --> 00:45:39,767
SO THIS SUGGESTS ALREADY THERE

1163
00:45:39,767 --> 00:45:41,936
MUST BE SOMETHING HAPPENING TO

1164
00:45:41,936 --> 00:45:43,537
THESE T-REGS THAT FIRST OF ALL

1165
00:45:43,537 --> 00:45:44,905
THEY START BECOMING LIKE AN

1166
00:45:44,905 --> 00:45:46,941
EFFECTOR CELL BECAUSE THEY MAKE

1167
00:45:46,941 --> 00:45:49,577
INTERFERON-GAMMA AND THE

1168
00:45:49,577 --> 00:45:50,044
PHENOTYPE IS CHANGING.

1169
00:45:50,044 --> 00:46:00,521
WHAT ABOUT THE IL12 THEY ARE

1170
00:46:07,528 --> 00:46:08,529
ACTUALLY LESS IMMUNOSUPPRESSIVE,

1171
00:46:08,529 --> 00:46:10,564
THEY MAKE MORE INTERFERON-GAMMA

1172
00:46:10,564 --> 00:46:12,633
AND SOMEHOW THEY ALSO LOSE

1173
00:46:12,633 --> 00:46:14,068
SUPPRESSOR FUNCTION EMPLOY NOW

1174
00:46:14,068 --> 00:46:15,536
WHAT ABOUT IL12.

1175
00:46:15,536 --> 00:46:19,506
IF WE USE ANTIIL12, WE ACTUALLY

1176
00:46:19,506 --> 00:46:23,644
LOSE THE EFFECT THAT WE GAIN BY

1177
00:46:23,644 --> 00:46:24,478
ADDING ANTIBGF, SO THERE SEEMS

1178
00:46:24,478 --> 00:46:26,380
TO BE ANOTHER CONNECTION THAT WE

1179
00:46:26,380 --> 00:46:27,715
HAD BASICEE PREDICTED BASED ON

1180
00:46:27,715 --> 00:46:28,415
OUR HUMAN DATA.

1181
00:46:28,415 --> 00:46:32,019
YOU CAN SEE FIRST A TUMOR SIZES

1182
00:46:32,019 --> 00:46:33,554
AND THE TUMOR WEIGHT AND THEN

1183
00:46:33,554 --> 00:46:36,090
AGAIN OUR CD8 T-CELLS ALL OF A

1184
00:46:36,090 --> 00:46:39,326
SUDDEN NO LONGER MAKE IL12,

1185
00:46:39,326 --> 00:46:42,730
SORRY THE T-REGS MAKE NO LONGER

1186
00:46:42,730 --> 00:46:44,164
LARGE AMOUNTS OF

1187
00:46:44,164 --> 00:46:48,068
INTERFERON-GAMMA THAT WE HAD

1188
00:46:48,068 --> 00:46:50,504
SEEN BEFORE AND THEY ALSO DON'T

1189
00:46:50,504 --> 00:46:51,538
CHANGE ANYMORE, DEDECREASE IS

1190
00:46:51,538 --> 00:46:53,674
NOT AS SIGNIFICANT AND WE DON'T

1191
00:46:53,674 --> 00:46:56,577
SEE A CHANGE IN T-BET.

1192
00:46:56,577 --> 00:47:02,716
SO IT HAD BEEN SUGGESTED BY

1193
00:47:02,716 --> 00:47:03,283
[INDISCERNIBLE]'S GROUP THE

1194
00:47:03,283 --> 00:47:05,019
NORMAL TISSUING REGS WE KNOW

1195
00:47:05,019 --> 00:47:08,622
EXPRESS A LOT OF Foxp3 AND ARE

1196
00:47:08,622 --> 00:47:10,624
IMMUNOSUPPRESSIVE AND BUT THEY

1197
00:47:10,624 --> 00:47:13,594
CAN CHANGE INTO FRAGILE AND

1198
00:47:13,594 --> 00:47:14,828
UNSTABLE TREGS, THEY LOSE

1199
00:47:14,828 --> 00:47:17,331
EXPRESSION OF Foxp3, THEY TART

1200
00:47:17,331 --> 00:47:18,599
TO RELEASE INTERFERON-GAMMA AND

1201
00:47:18,599 --> 00:47:24,104
THEY  CHANGE EXPRESSION AND

1202
00:47:24,104 --> 00:47:33,781
EXPRESS Foxp3 AND START TO

1203
00:47:33,781 --> 00:47:34,615
BECOME LESS IMMUNOSUPPRESSIVE.

1204
00:47:34,615 --> 00:47:36,216
SO IF THIS IS TRUE WE SHOULD SEE

1205
00:47:36,216 --> 00:47:37,618
THIS IN OUR PATES.

1206
00:47:37,618 --> 00:47:48,062
SO NOW WE WENT BACK TO THE

1207
00:47:48,362 --> 00:47:49,596
PATIENTS, WE AND WHAT I'M DOING

1208
00:47:49,596 --> 00:47:51,732
HERE NOW IS THIS IS ALMOST THE

1209
00:47:51,732 --> 00:47:53,233
LAST SLIDE, WE LOOKED AT THE

1210
00:47:53,233 --> 00:47:54,635
EFFECT ISSUES WE SPECIFICALLY

1211
00:47:54,635 --> 00:47:59,239
ZOOM IN ON THE TREGS AND PREAND

1212
00:47:59,239 --> 00:48:01,875
POST TREATMENT ASK WE SEE THAT

1213
00:48:01,875 --> 00:48:03,944
THESE TREGS DON'T CLUSTER INTO 1

1214
00:48:03,944 --> 00:48:04,144
GROUP.

1215
00:48:04,144 --> 00:48:07,247
CAN YOU SEE THERE IS THE--THERE

1216
00:48:07,247 --> 00:48:08,449
ARE DIFFERENT SUBSES, SOME FOR

1217
00:48:08,449 --> 00:48:10,951
INSTANCE IF YOU LOOK AT CTLA-4,

1218
00:48:10,951 --> 00:48:12,753
THEY ARE THE STONES, THE SAME

1219
00:48:12,753 --> 00:48:15,589
APPLIES TO STAT 1 OR YOU KNOW

1220
00:48:15,589 --> 00:48:16,590
MANY OF THE OTHER MOLECULES THAT

1221
00:48:16,590 --> 00:48:18,792
YOU WANT TO LOOK AT AND IF WE DO

1222
00:48:18,792 --> 00:48:20,461
THIS, LOOK IN MORE DETAIL, WE

1223
00:48:20,461 --> 00:48:26,233
CAN ACTUALLY E DENTIFY HERE, THE

1224
00:48:26,233 --> 00:48:27,201
DIFFERENT T-CELL SUBSETS, THE

1225
00:48:27,201 --> 00:48:28,202
NTEGGIC--STRATEGIC REGS WHICH

1226
00:48:28,202 --> 00:48:30,137
ARE THE NATURAL TREGS WE BELIEVE

1227
00:48:30,137 --> 00:48:33,741
ARE VERY IMMUNOSUPPRESSIVE BUT

1228
00:48:33,741 --> 00:48:37,244
ALSO THE FRAGILE T-REGS AND THE

1229
00:48:37,244 --> 00:48:38,445
UTREGS, THE UNSTABLE TREGS, THIS

1230
00:48:38,445 --> 00:48:40,848
IS NOW THE ANALYSIS FROM ALL

1231
00:48:40,848 --> 00:48:45,018
THESE PATIENTS BEFORE AND AFTER

1232
00:48:45,018 --> 00:48:47,921
AND INTERESTINGLY IF WE COMPARE

1233
00:48:47,921 --> 00:48:49,556
PRE VERSUS POST, YOU CAN SEE

1234
00:48:49,556 --> 00:48:50,390
THAT THE RED CLUSTER GETS

1235
00:48:50,390 --> 00:48:54,394
SMALLER EMPLOY THESE ARE THE

1236
00:48:54,394 --> 00:48:56,130
NTREGS, THE UTREGS, THE GREEN 1

1237
00:48:56,130 --> 00:48:58,499
AS WELL AS FRAGILE TREGS, THESE

1238
00:48:58,499 --> 00:49:00,234
ARE THE 1S THAT MAKE MORE

1239
00:49:00,234 --> 00:49:01,668
INTERFERON-GAMMA AND THAT LOSES

1240
00:49:01,668 --> 00:49:04,738
SUPPRESSOR FUNCTION INCREASE IN

1241
00:49:04,738 --> 00:49:05,472
THESE PATIENTS.

1242
00:49:05,472 --> 00:49:06,974
AND THEN AGAIN, I KNOW YOU ARE

1243
00:49:06,974 --> 00:49:09,576
ALL DOING SINGLE CELL ANALYSIS

1244
00:49:09,576 --> 00:49:12,045
AND YOU DO THIS ALL THE TIME, SO

1245
00:49:12,045 --> 00:49:14,181
LINEAGE COMMITMENT AND WOE SEE

1246
00:49:14,181 --> 00:49:20,053
THAT INDEED, IN THE PATIENTS

1247
00:49:20,053 --> 00:49:22,556
THESE CELLS--THESE FRAGILE TREGS

1248
00:49:22,556 --> 00:49:25,425
AS WELL AS UTREGS CAME OUT OF

1249
00:49:25,425 --> 00:49:30,164
THE  NTREG.

1250
00:49:30,164 --> 00:49:32,299
SO LET ME SUMMARIZE THE LAST

1251
00:49:32,299 --> 00:49:34,334
PART. 

1252
00:49:34,334 --> 00:49:36,970
THE COMBINATION OF ANTIBGF, AND

1253
00:49:36,970 --> 00:49:39,673
THIS EVOKED VERY IMPORTANT

1254
00:49:39,673 --> 00:49:40,107
ANTITUMOR IMMUNITY.

1255
00:49:40,107 --> 00:49:43,477
I'VE SHOWN YOU THAT THE ADDITION

1256
00:49:43,477 --> 00:49:47,080
OF THE VEGF INCREASED SYSTEMIC

1257
00:49:47,080 --> 00:49:50,184
IERK L12 AND THIS LEADS TO AN

1258
00:49:50,184 --> 00:49:52,052
IL12 DEPENDENT CHANGE IN TREGS

1259
00:49:52,052 --> 00:49:56,156
WITH AN INCREASE IN FRAGILE AND

1260
00:49:56,156 --> 00:49:57,925
UNSTABLE TREGS.

1261
00:49:57,925 --> 00:50:02,329
SO WITH THIS, I WILL LIKE TO

1262
00:50:02,329 --> 00:50:05,732
CLOSE AND NEED TO THANK THE

1263
00:50:05,732 --> 00:50:08,735
GROUP, BUT BEFORE I THANK THE

1264
00:50:08,735 --> 00:50:09,837
GROUP THAT'S PRESENT, I THINK

1265
00:50:09,837 --> 00:50:11,338
IT'S IMPORTANT TO SPEBD A BRIEF

1266
00:50:11,338 --> 00:50:12,840
MOMENT TO THANK ALL THE PEOPLE

1267
00:50:12,840 --> 00:50:14,341
THAT GENERATE THIS DATA AND

1268
00:50:14,341 --> 00:50:18,812
ALREADY LEFT MY LAB AS WELL AS

1269
00:50:18,812 --> 00:50:20,247
THE TREMENDOUS CLINICAL SUPPORT,

1270
00:50:20,247 --> 00:50:21,648
WITHOUT THEM IT WOULD BE

1271
00:50:21,648 --> 00:50:25,285
IMPOSSIBLE TO DO THESE STUDIES

1272
00:50:25,285 --> 00:50:26,587
BOTHOT CLINICAL SIDE AS WELL AS

1273
00:50:26,587 --> 00:50:28,222
ON THE SIDE THAT WE NEED, YOU

1274
00:50:28,222 --> 00:50:31,024
KNOW ADMIN TRAITIVE SIDE TO DO

1275
00:50:31,024 --> 00:50:32,893
TRIAL SUPPORT.

1276
00:50:32,893 --> 00:50:37,030
AND THEN OBVIOUSLY, FOR THE

1277
00:50:37,030 --> 00:50:39,600
SCIENCE PART THE MANY, MANY

1278
00:50:39,600 --> 00:50:40,968
DIFFERENT NIH COLLABORATORS THAT

1279
00:50:40,968 --> 00:50:44,338
HELP WITH DIFFERENT ASPECTS OF

1280
00:50:44,338 --> 00:50:45,172
MICROBIOME AND OBVIOUSLY LIVER

1281
00:50:45,172 --> 00:50:48,709
CANCER AND IMAGING, I MENTIONED,

1282
00:50:48,709 --> 00:50:53,313
ET CETERA, THE VARIOUS CORE

1283
00:50:53,313 --> 00:50:54,815
FACILITIES, BIOINFORMATTIC

1284
00:50:54,815 --> 00:50:56,917
RESOURCES THAT HELP, EXTRAMURAL

1285
00:50:56,917 --> 00:50:58,218
COLLABORATORS AND OBVIOUSLY LAST

1286
00:50:58,218 --> 00:50:59,786
BUT NOT LEAST ALSO ADDITIONAL

1287
00:50:59,786 --> 00:51:02,522
FUNDING THAT I WAS ABLE TO

1288
00:51:02,522 --> 00:51:03,690
COLLECT THAT MADE THESE STUDIES

1289
00:51:03,690 --> 00:51:04,892
POSSIBLE AND WITH THIS, I AM

1290
00:51:04,892 --> 00:51:13,333
HAPPY TO TAKE ANY QUESTIONS. 

1291
00:51:13,333 --> 00:51:19,606
KD--SALLY ASH PLAWZ

1292
00:51:19,606 --> 00:51:21,208
>> OVER HERE EMPLOY
BEAUTIFUL

1293
00:51:21,208 --> 00:51:21,675
STORY.

1294
00:51:21,675 --> 00:51:22,976
ONE QUESTION, COMMENT ABOUT THE

1295
00:51:22,976 --> 00:51:26,380
LAST PART OF THE STORY WITH THE

1296
00:51:26,380 --> 00:51:27,180
ANTIVEGF.

1297
00:51:27,180 --> 00:51:30,817
SO AS YOU KNOW VEGF ITSELF

1298
00:51:30,817 --> 00:51:34,688
INDUCES AT THAT TIME 3 AND

1299
00:51:34,688 --> 00:51:36,490
ANOTHER CYTOKINE THAT INDUCES

1300
00:51:36,490 --> 00:51:38,792
STAT 3 AND IL10 WHICH KNOWN TO

1301
00:51:38,792 --> 00:51:44,364
INHIBIT PRODUCTION  OF IL12.

1302
00:51:44,364 --> 00:51:48,268
SO 1 MIGHT EMBASSY THAT VEGF

1303
00:51:48,268 --> 00:51:53,273
COULD INHIBIT IL12 AND THEREFORE

1304
00:51:53,273 --> 00:51:54,675
ANTIVEGF MIGHT PROMOTE MORE IL12

1305
00:51:54,675 --> 00:51:57,110
PRODUCTION WHICH WOULD INDUCE

1306
00:51:57,110 --> 00:51:58,245
T-BET AND INTERFERON-GAMMA

1307
00:51:58,245 --> 00:52:02,249
PRODUCTION AND SO FORTH BY THE

1308
00:52:02,249 --> 00:52:02,482
TREGS.

1309
00:52:02,482 --> 00:52:05,786
SO CAN YOU LOOK TO SEE WHETHER

1310
00:52:05,786 --> 00:52:10,290
THE PHOSPHORYLATION OF STAT 3

1311
00:52:10,290 --> 00:52:17,564
PLAYS A ROLE IN THIS PROCESS

1312
00:52:17,564 --> 00:52:18,932
THAT YOU DESCRIBED?

1313
00:52:18,932 --> 00:52:19,800
>> SO HAD IS THE NICE
THING

1314
00:52:19,800 --> 00:52:21,134
ABOUT THE MOUSE FORM AND WHY I

1315
00:52:21,134 --> 00:52:22,769
LIKE THESE TYPE OF STUDIES,

1316
00:52:22,769 --> 00:52:24,638
REMEMBER WE ONLY HAD 7 PATIENTS

1317
00:52:24,638 --> 00:52:26,440
AND YES, IN MICE WE CAN DO

1318
00:52:26,440 --> 00:52:27,708
EVERYTHING, YOU KNOW WE CAN LOOK

1319
00:52:27,708 --> 00:52:29,309
AT STAT 3 BECAUSE THESE

1320
00:52:29,309 --> 00:52:31,278
EXPERIMENTS ARE NOW RELATIVELY

1321
00:52:31,278 --> 00:52:31,745
EASY TO DO.

1322
00:52:31,745 --> 00:52:33,647
SO AS I MENTIONED, AS YOU KNOW

1323
00:52:33,647 --> 00:52:35,248
BECAUSE WE ACTUALLY HAVE A

1324
00:52:35,248 --> 00:52:36,984
SHARED LAB MEETING FOR EVERYBODY

1325
00:52:36,984 --> 00:52:38,952
ELSE, SO YOU KNOW JAY ACTUALLY

1326
00:52:38,952 --> 00:52:42,789
KNOWS ALL THIS DATA, OBVIOUSLY,

1327
00:52:42,789 --> 00:52:45,325
YOU KNOW WE CAN DECIPHER THIS IN

1328
00:52:45,325 --> 00:52:46,793
MORE DETAIL TO SEE WITH THE IL10

1329
00:52:46,793 --> 00:52:54,434
PLAYS A ROLE IN THIS. 

1330
00:52:54,434 --> 00:52:56,303
>> OKAY, THANKS.

1331
00:52:56,303 --> 00:52:59,272
>> HI DR. GRETEN, I VERY
MUCH

1332
00:52:59,272 --> 00:53:01,274
ENJOYED YOUR TALK AS I DID AS MY

1333
00:53:01,274 --> 00:53:03,910
TIME IN YOUR CLINIC AS AA

1334
00:53:03,910 --> 00:53:04,144
TRAINEE.

1335
00:53:04,144 --> 00:53:07,314
MY QUESTION HAS TO DO WITH

1336
00:53:07,314 --> 00:53:09,049
INNATE CELL INHIBITION GROWTH.

1337
00:53:09,049 --> 00:53:19,559
DO THE MAIT CELLS POSSESS THE

1338
00:53:21,228 --> 00:53:22,396
CAPACITY FOR METASTASIS AND ALSO

1339
00:53:22,396 --> 00:53:26,266
DO THEY HAVE THE SAME WITH THE

1340
00:53:26,266 --> 00:53:29,936
SCLEROTICS LIVER WITH THE

1341
00:53:29,936 --> 00:53:30,704
COLORECTAL MEDS?

1342
00:53:30,704 --> 00:53:30,971
THANK YOU.

1343
00:53:30,971 --> 00:53:34,708
>> O THAT IS OBVIOUSLY A
VERY

1344
00:53:34,708 --> 00:53:37,677
GOOD QUESTION AND PART OF THE

1345
00:53:37,677 --> 00:53:39,679
MATTER OR ABILITY OR YOB IS TO

1346
00:53:39,679 --> 00:53:44,518
PROVIDE YOUR FELLOWS WITH GOOD

1347
00:53:44,518 --> 00:53:46,753
PROJECTS.

1348
00:53:46,753 --> 00:53:47,721
[LAUGHTER]

1349
00:53:47,721 --> 00:53:48,522
>> THANK YOU.

1350
00:53:48,522 --> 00:53:49,956
>> SO THIS POST DOC LEFT
AND

1351
00:53:49,956 --> 00:53:52,025
STARTED HIS OWN LAB, HE'S GOING

1352
00:53:52,025 --> 00:53:53,060
TO STUDY NOT WHAT YOU PROPOSE

1353
00:53:53,060 --> 00:53:54,828
BUT HE WILL IS ITED THIS IN THE

1354
00:53:54,828 --> 00:53:56,496
CONTEXT OF LIVER DEC AND FATTY

1355
00:53:56,496 --> 00:53:58,131
LIVER DISEASE WHICH KIND OF WHAT

1356
00:53:58,131 --> 00:53:59,566
YOU SUGGEST, AND YOU KNOW I LET

1357
00:53:59,566 --> 00:54:01,501
THEM DO THE STUDIES.

1358
00:54:01,501 --> 00:54:03,737
IF YOU WANTED TO STUDY THIS IN

1359
00:54:03,737 --> 00:54:06,506
THE CO KNOW SEPTORS, WE BEING

1360
00:54:06,506 --> 00:54:14,448
POTENTIALLY DO THIS, TOO. 

1361
00:54:14,448 --> 00:54:15,148
>> THANK YOU.

1362
00:54:15,148 --> 00:54:16,316
>> ALWAYS A HUGE PLEASURE
AND

1363
00:54:16,316 --> 00:54:17,884
I'M EYE HUGE FAN OF TIM'S WORK

1364
00:54:17,884 --> 00:54:19,586
SO IT'S GREAT TO BE HERE.

1365
00:54:19,586 --> 00:54:20,821
THANK YOU SO MUCH.

1366
00:54:20,821 --> 00:54:23,490
I HAVE A QUESTION WHICH MAY BE 1

1367
00:54:23,490 --> 00:54:26,059
OF IGNORANCE BUT IN THE CONTEXT

1368
00:54:26,059 --> 00:54:28,328
OF THE MAIT CELLS AND THINKING

1369
00:54:28,328 --> 00:54:29,930
ABOUT THE MICROBI OTA DO YOU

1370
00:54:29,930 --> 00:54:31,064
KNOW HOW RIBOFLAVORIN LEVELS

1371
00:54:31,064 --> 00:54:32,632
PLAY A ROLE IN ALL THIS AND

1372
00:54:32,632 --> 00:54:35,702
COULD YOU MANIPULATE THAT?

1373
00:54:35,702 --> 00:54:35,936
RIGHT?

1374
00:54:35,936 --> 00:54:36,169
>>

1375
00:54:36,169 --> 00:54:39,206
>> YEAH, NO, I KNOW.

1376
00:54:39,206 --> 00:54:40,707
SO FIRST OF ALL I DON'T KNOW.

1377
00:54:40,707 --> 00:54:41,408
THAT'S NUMBER 1.

1378
00:54:41,408 --> 00:54:43,944
WE KNOW THAT, YOU KNOW FROM

1379
00:54:43,944 --> 00:54:45,912
JASMINE'S WORK THAT YOU NEED THE

1380
00:54:45,912 --> 00:54:47,681
GUT MICROBIOME TO HAVE THE

1381
00:54:47,681 --> 00:54:50,217
MAITs, AND YOU KNOW THIS, BUT

1382
00:54:50,217 --> 00:54:51,351
THE AUDIENCE PROBABLY DOESN'T

1383
00:54:51,351 --> 00:54:54,321
KNOW THIS IS IT'S VERY DIFFICULT

1384
00:54:54,321 --> 00:54:56,189
TO STUDY MAITs IN MICE,

1385
00:54:56,189 --> 00:55:00,193
BECAUSE THEY DON'T HAVE A LOT OF

1386
00:55:00,193 --> 00:55:01,761
NKT CELLS, IT'S HUMANS THAT HAVE

1387
00:55:01,761 --> 00:55:03,363
THE MAITs, YOU KNOW I KIND OF

1388
00:55:03,363 --> 00:55:04,498
DISMISS THAD PART SO IT'S REALLY

1389
00:55:04,498 --> 00:55:07,901
DIFFICULT TO DO THOSE STUDIES

1390
00:55:07,901 --> 00:55:09,736
WHY JUST BECAUSE THERE'S SUCH

1391
00:55:09,736 --> 00:55:12,005
FEW CELLS.

1392
00:55:12,005 --> 00:55:14,074
N[INAUDIBLE RESPONSE FROM

1393
00:55:14,074 --> 00:55:14,441
AUDIENCE ]

1394
00:55:14,441 --> 00:55:15,942
>> WE HAVEN'T LOOKEDDA THE
THIS

1395
00:55:15,942 --> 00:55:19,679
BUT WHAT WE'RE BASICALLY--WE

1396
00:55:19,679 --> 00:55:19,980
DON'T KNOW.

1397
00:55:19,980 --> 00:55:20,914
BUT WHAT WE'RE TRYING TO DO NOW

1398
00:55:20,914 --> 00:55:22,883
IS, YOU KNOW WE ARE TRYING TO

1399
00:55:22,883 --> 00:55:25,318
FIND ALTERNATE WAYS TO INDUCE

1400
00:55:25,318 --> 00:55:28,688
MAITs AND THEN RATHER

1401
00:55:28,688 --> 00:55:29,956
INDEPENDENT OF [INDISCERNIBLE]

1402
00:55:29,956 --> 00:55:33,260
TO USE THEM AS A TOOL TO INDUCE

1403
00:55:33,260 --> 00:55:35,629
ANTITUMOR IMMUNITY.

1404
00:55:35,629 --> 00:55:39,799
>> LET ME ASK YOU 1
QUESTION,

1405
00:55:39,799 --> 00:55:41,735
STEMMED FROM THE LAST QUESTION

1406
00:55:41,735 --> 00:55:44,070
AS AN EXTENSION, MORE AS A

1407
00:55:44,070 --> 00:55:44,304
GLOBAL.

1408
00:55:44,304 --> 00:55:48,241
SO YOU FIND PLATELETS FOR

1409
00:55:48,241 --> 00:55:51,044
SIGNALING, YOU ALSO FIND THE

1410
00:55:51,044 --> 00:55:55,649
MAITs FOR SIGNALING AND IN THE

1411
00:55:55,649 --> 00:55:57,417
MICROBIOME AS WELL, BUT IT STEMS

1412
00:55:57,417 --> 00:55:59,519
FROM DISEASE AND MULTIPLE

1413
00:55:59,519 --> 00:56:00,287
IMMUNOLOGYS THAT CONTRIBUTE AND

1414
00:56:00,287 --> 00:56:02,556
HOW DO YOU SEE THAT IF IT'S A

1415
00:56:02,556 --> 00:56:03,490
DIFFERENT CONNECTION THAT HELP

1416
00:56:03,490 --> 00:56:05,091
TO IMPROVE THE TREATMENT,

1417
00:56:05,091 --> 00:56:09,496
WHETHER THEY'RE FUNCTIONAL AT

1418
00:56:09,496 --> 00:56:10,096
LENGTH NOW.

1419
00:56:10,096 --> 00:56:11,464
>> WELL OBVIOUSLY ANY OF
THESE

1420
00:56:11,464 --> 00:56:12,999
SHOW THE MECHANISM OF SPECIFIC

1421
00:56:12,999 --> 00:56:14,501
SECTOR AND IN THE END, YES, THE

1422
00:56:14,501 --> 00:56:17,237
QUESTION IS YOU KNOW HOW YOU--IN

1423
00:56:17,237 --> 00:56:18,672
THE END THE PERSON WHO WINS IS

1424
00:56:18,672 --> 00:56:21,708
THE 1 WHO TREATS THE PATIENT AND

1425
00:56:21,708 --> 00:56:22,809
THE PATIENT RESPONDS.

1426
00:56:22,809 --> 00:56:23,243
THERE'S NO QUESTION.

1427
00:56:23,243 --> 00:56:25,345
BUT IN THE END AUTOWHAT'S MOST

1428
00:56:25,345 --> 00:56:26,046
IMPORTANT AND SIGNIFICANT.

1429
00:56:26,046 --> 00:56:27,180
AND THE IT'S A DIFFICULT

1430
00:56:27,180 --> 00:56:28,248
QUESTION AND A LONG QUESTION BUT

1431
00:56:28,248 --> 00:56:30,016
I DO HAVE IDEAS ABOUT THIS.

1432
00:56:30,016 --> 00:56:33,019
IT'S NOT THAT I WANT TO RUN AWAY

1433
00:56:33,019 --> 00:56:34,354
FROM THIS, I THINK A LOT OF THE

1434
00:56:34,354 --> 00:56:37,290
WORK THAT'S GOING ON RIGHT NOW

1435
00:56:37,290 --> 00:56:38,825
IS VERY T-CELL CENTRIC AND

1436
00:56:38,825 --> 00:56:40,827
THAT'S BECAUSE PEOPLE LIKE

1437
00:56:40,827 --> 00:56:41,695
T-CELLS, WE HAVE STUDIED T-CELLS

1438
00:56:41,695 --> 00:56:44,364
FOR A LONG TIME AND WE CHECK

1439
00:56:44,364 --> 00:56:45,532
POINT INHIBITORS, SO THAT'S WHY

1440
00:56:45,532 --> 00:56:47,167
PEOPLE STUDY THEM CAN WE TRY TO

1441
00:56:47,167 --> 00:56:49,436
STUDY THEM AS LITTLE AS POSSIBLE

1442
00:56:49,436 --> 00:56:51,071
BECAUSE THERE'S MANY OTHER VERY

1443
00:56:51,071 --> 00:56:52,505
IMPORTANT IMMUNE CELLS THAT ARE

1444
00:56:52,505 --> 00:56:53,573
DISMISSED AND THAT'S WHAT I TRY

1445
00:56:53,573 --> 00:56:59,512
TO SHOW YOU HERE IN THE END, SO

1446
00:56:59,512 --> 00:57:00,146
IF YOU ARE REALLY ASKING ME FROM

1447
00:57:00,146 --> 00:57:01,514
A BIG PICTURE, THE MYELOID

1448
00:57:01,514 --> 00:57:04,317
COMPARTMENT, I SHOWED YOU THE

1449
00:57:04,317 --> 00:57:05,252
TUMOR ASSOCIATED MACROPHAGES CHU

1450
00:57:05,252 --> 00:57:08,054
ONLY FIND IN THE SURROUNDING

1451
00:57:08,054 --> 00:57:08,989
TISSUE UPREGULATING PDL1, OUR

1452
00:57:08,989 --> 00:57:10,023
CERTAINTY IN CELL POPULATION

1453
00:57:10,023 --> 00:57:12,826
WHICH IS OF GREAT INTEREST,

1454
00:57:12,826 --> 00:57:13,793
THEY'RE VERY IMMUNOSUPPRESSIVE

1455
00:57:13,793 --> 00:57:15,795
AND THE SAME AMRIS TO REGULATORY

1456
00:57:15,795 --> 00:57:16,763
T-CELLS, WE HAVE ANOTHER STUDY

1457
00:57:16,763 --> 00:57:18,598
WHERE WE LACK THEA REGULATORY

1458
00:57:18,598 --> 00:57:20,400
T-CELLS WE KNOW THESE ARE MANY,

1459
00:57:20,400 --> 00:57:22,168
MANY YORES, WE ARE JUST NOT ABLE

1460
00:57:22,168 --> 00:57:24,204
TO SPECIFICALLY TARGET AND

1461
00:57:24,204 --> 00:57:24,938
ELIMINATE THEM.

1462
00:57:24,938 --> 00:57:28,742
WE DO THIS BY EXITING AND USING

1463
00:57:28,742 --> 00:57:29,309
ANTIVEGF, WE HAVE DRAMATIC

1464
00:57:29,309 --> 00:57:29,976
CENTER FOR EXCELLENCE ON AGINGS

1465
00:57:29,976 --> 00:57:31,678
BUT I THINK WHAT THE FIELD

1466
00:57:31,678 --> 00:57:33,947
REALLY HAS TO LEARN AND DO A

1467
00:57:33,947 --> 00:57:36,683
LITTLE BIT IS TRY TO FIND MORE

1468
00:57:36,683 --> 00:57:38,551
SIGNIFICANT CHANGES, RATHER THAN

1469
00:57:38,551 --> 00:57:39,319
THIS INCREMENTAL CHANGES USING

1470
00:57:39,319 --> 00:57:44,024
WHAT I DID MYSELF, ADDING PDL1

1471
00:57:44,024 --> 00:57:47,227
AND CTLA-4, GO FOR THE BIG

1472
00:57:47,227 --> 00:57:47,460
CHANGE.

1473
00:57:47,460 --> 00:57:51,031
NOKAY, WELL THIS IS A PERFECT

1474
00:57:51,031 --> 00:57:53,500
WRAP UP OF WHAT IS A FANTASTIC

1475
00:57:53,500 --> 00:57:53,800
GRAND ROUND.

1476
00:57:53,800 --> 00:58:03,800
THANK YOU VERY MUCH, TIM.