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Overcoming chronic inflammation-driven T cell quiescence in gastric adenocarcinoma

Award Number: R01CA308278
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Overcoming chronic inflammation-driven T cell quiescence in gastric adenocarcinoma - PROJECT SUMMARY Gastric cancer is the 5th most common cause of death worldwide with an incidence that is rising, particularly among adults younger than 40, underscoring the need to identify targetable drivers of gastric cancer development and progression. Chronic inflammation, due either to infectious or autoimmune etiologies, is amongst the strongest risk factors for the development of gastric cancer. Yet, despite high levels of inflammation, gastric cancers are marked by poor levels of T-cell surveillance. As such, most gastric tumors exhibit minimal or no response to immune checkpoint blockade. How persistent innate inflammation suppresses T-cell immunity in gastric cancer remains poorly understood. Our individual research groups have extensive experience in single cell genomics, cancer evolution, T-cell biology, and clinical outcomes in gastric cancer. We previously found that T-cell infiltration and differentiation within gastric tumors was significantly influenced by the relative success with which T-cells are primed in gastric tumor-draining lymph nodes. In exciting preliminary data, we profiled paired tumors and tumor-draining lymph nodes from patients with both early and advanced stage gastric cancer and found that chronic inflammation significant alters T-cell priming within tumor draining lymph nodes, through effects on both antigen presentation and stabilization of the quiescence-associated transcription factor KLF-2 in primed T-cells. Our findings raise the possibility that chronic inflammation promotes gastric tumorigenesis by inducing KLF-2- dependent T-cell sequestration and quiescence in tumor-draining lymph nodes. The goal of this project is to determine how chronic inflammation-dependent KLF-2 induction suppresses anti-tumor immunity in gastric cancer. We hypothesize that KLF-2 is preferentially induced in lymph node-resident T-cells from gastric cancers with high levels of innate inflammation, and this limits cytotoxic T-cell differentiation and tissue infiltration. To test this hypothesis, we will determine which gastric cancer-driven inflammatory factors drive KLF-2 expression in T-cells (Aim 1), define how KLF-2 stabilization alters T-cell differentiation and tissue residence in gastric cancer (Aim 2), and determine whether manipulating KLF-2 expression, either directly or by targeting myeloid inflammation, can restore anti-tumor immunity in gastric cancer (Aim 3). If successful, the proposed experiments will reveal the mechanism by which chronic inflammation leads to T-cell suppression during gastric tumorigenesis and nominate rational strategies to enhance anti-tumor immunity and response to immune checkpoint blockade in this increasingly prevalent malignancy.


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: 2026 ( Subtotal = $730,097 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	000	1	4/6/2026	NEW	$730,097
														Subtotal = $730,097

Grand Total All Awards = $730,097

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Overcoming chronic inflammation-driven T cell quiescence in gastric adenocarcinoma

Award Number: R01CA308278

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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