Dysfunctional CD8 T cells in tumors are addicted to antigen

Chronic antigen stimulation, as during cancer or chronic infection, leads to T cell dysfunction. We studied the impact of chronic antigen stimulation on T cell receptor (TCR) signaling in CD8 T cells using a genetic liver cancer mouse model. Tumor-specific CD8 T cells (TST) initially acquired proximal TCR signaling defects, but with increased antigen exposure showed both proximal and distal signaling defects. Despite impaired TCR signaling, a stable population of TST was maintained throughout tumorigenesis. We tried to rescue dysfunctional TST by removing them from tumors but found that TST failed to survive in tumor-free mice; thus, T cells are addicted to antigen, though antigen impairs TCR signaling. We investigated the mechanism of antigen-dependent TST persistence and found that throughout tumorigenesis, a subset of terminally-differentiated (TCF1-) TST within liver tumors could be found in cell cycle. The proliferation-associated distal TCR signaling pathways MAPK and mTOR were impaired in TCF1- TST, and we hypothesize that antigen-dependent persistence is NFAT-dependent. Studies are underway to determine whether all TCF1- TST can enter cell cycle in a stochastic, NFAT-driven manner, or if only a specific subset of TCF1- TST proliferate. By understanding how T cell signaling is regulated in response to chronic antigen stimulation, we can design strategies to selectively modulate TCR signaling to maintain proliferation while preventing loss of effector function.