Abstract IA02: Mechanisms of TCF1 regulation of stem-like T cells in cancer and autoimmunity

Abstract TCF1 has emerged as a critical regulator of T cells that retain features of stemness. In cancer, we and others have shown that TCF1+ CD8+ stem-like T cells are important for sustaining response to checkpoint blockade and other immune-harnessing therapies. In the absence of TCF1 in CD8+ T cells, responses to immunotherapy are limited, but the reliance on TCF1 is not uniform across tumor contexts. We have found that TCF1 is critical for response to immunotherapy in settings of low TCR affinity for tumor specific-antigen and/or low tumor antigenicity. This reflects a role for TCF1 in ensuring optimal priming to low TCR triggering in the tumor-draining lymph node, which in turn, ensures the generation of TIL better fit to survive in the tumor microenvironment (TME). In autoimmunity, we have examined a role for TCF1 in CD4+ IL-17-producing (Th17) T cells that are key drivers of autoimmune tissue inflammation in multiple disease contexts. We have found that TCF1 is more highly expressed in stem-like Th17 that preserve tissue homeostasis compared to pro-inflammatory Th17 that drive autoimmune tissue destruction. We uncover that IL-23, an essential cytokine driver of pro-inflammatory Th17, decreases TCF1, which regulates the homeostatic to pro-inflammatory Th17 cell state transition through orchestration of a regulatory network that maintains homeostatic Th17 cell state and binds to and restrains the activity of RORgt. Our findings highlight the cell context-specific mechanisms employed by TCF1 in T cell subsets in cancer and autoimmunity and shed light on potential mechanisms underlying the association of genetic variants in TCF1 with susceptibility to disease in humans. Citation Format: Ana C. Anderson. Mechanisms of TCF1 regulation of stem-like T cells in cancer and autoimmunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr IA02.