Overcoming chronic inflammation-driven T cell quiescence in gastric adenocarcinoma

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. Project Number: 1R01CA308278-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: SANTOSHA VARDHANA (+2 co-PIs) | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $730,097 | Activity Code: R01 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11278948