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Unraveling the Role of PD-1 in CD8+ Tissue-Resident Memory T Cell Homeostasis and Epithelial Damage in Human Colitis

Award Number: K08DK127246
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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Unraveling the Role of PD-1 in CD8+ Tissue-Resident Memory T Cell Homeostasis and Epithelial Damage in Human Colitis - Project Summary Monoclonal antibodies against co-inhibitory immune receptors PD-1 and CTLA-4 [immune checkpoint inhibitors (ICIs)] have revolutionized immuno-oncology by reversing T cell exhaustion and harnessing the power of the immune system to fight solid tumors. Although ICI therapy has improved the survival of patients with metastatic cancer, treatments are unfortunately limited by the development of immune-related adverse events. Colitis is the most common, severe side effect of ICIs – seen in 5-10% of patients on PD-1 and up to 50% of patients on dual PD-1/CTLA-4 blockade – and is marked by epithelial injury and apoptosis. To date, little is understood about the immunologic underpinnings of PD-1 colitis, in part because mice treated with PD-1-blocking antibodies do not readily develop gastrointestinal toxicities. This proposal presents a five-year research career development program focused on understanding the immune drivers of human colitis that develops after PD-1 blockade [i.e., immunotherapy-related colitis (irColitis)]. Dr. Molly Thomas is an Instructor of Medicine at Harvard Medical School in the Division of Gastroenterology at Massachusetts General Hospital. This award will provide Dr. Thomas with the support necessary to test the hypothesis that irColitis is caused by the expansion of specific colon CD8+ T-resident memory (Trm) cells into cytotoxic effectors that produce IL-26 and IL-17A and home directly to damaged epithelium where they have deleterious effects on epithelial turnover and absorptive function. This hypothesis will be tested through the following aims: (Aim 1) Define the epigenetic landscapes and effector functions of distinct colonic CD8+ Trm and Trm-derived effectors; (Aim 2) Determine if CD8+ T effectors detected in the colon mucosa of irColitis patients circulate in blood and which blood immune cell states track with disease; (Aim 3) Map interactions between CD8+ Trms and damaged epithelial cells to understand how PD-1 inhibition leads to interferon-dependent defects in CD8+ Trm homing and epithelial absorptive function. Through these proposed aims, Dr. Thomas will map the complex interactions between CD8+ Trms and damaged colonic epithelium following PD-1 blockade. She will work under the guidance of her primary mentor Dr. Nir Hacohen, an expert in immuno-oncology and autoimmunity, and her co-mentor Dr. Alexandra-Chloé Villani, an expert in leveraging single cell genomics to understand immune heterogeneity in health and disease. The proposed experiments, analyses, and didactic work will provide Dr. Thomas with a unique set of skills that will enable her to transition to independence as a physician-scientist studying immune- mediated gastrointestinal diseases. These studies will define mechanisms by which IL-26+ and IL-17A+ CD8+ T cell effectors orchestrate pathologic inflammation and will allow for the development of diagnostic tools and treatment strategies that will be broadly applicable to irColitis patients and those with inflammatory bowel disease. By year four of this five-year award, Dr. Thomas will be well-positioned to develop an R01 application to define pathologic Trm responses in the human gastrointestinal tract and therapeutic targets to treat irColitis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $172,800 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/18/2025	NON-COMPETING CONTINUATION	$172,800
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	2/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$134,602
2025	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/25/2025	NON-COMPETING CONTINUATION	-$134,602
														Subtotal = $172,800

Issue Date FY: 2024 ( Subtotal = $172,800 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$172,800
2024	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $172,800

Issue Date FY: 2023 ( Subtotal = $172,800 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/27/2023	NON-COMPETING CONTINUATION	$172,800
														Subtotal = $172,800

Issue Date FY: 2022 ( Subtotal = $172,440 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/30/2022	NEW	$172,440
														Subtotal = $172,440

Grand Total All Awards = $690,840

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Unraveling the Role of PD-1 in CD8+ Tissue-Resident Memory T Cell Homeostasis and Epithelial Damage in Human Colitis

Award Number: K08DK127246

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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