TCF1 lo CD8 T cells proliferate and persist autonomously in tumors

ABSTRACT Cancers develop in humans over months to years, and tumor-specific CD8 T cells (TST) can interact with cancer cells throughout tumorigenesis. Nevertheless, the long-term population dynamics of TST, especially within progressing tumors, are not well understood. A paradigm first established in chronic viral infection and applied to tumors describes a population hierarchy among exhausted T cells. Progenitor/stem-like exhausted T cells, which express the transcription factor T cell factor 1 (TCF1), maintain the population through self-renewal and by giving rise to terminally differentiated TCF1 lo progeny. This has led to a focus on TCF1 hi T cells, and though TCF1 lo CD8 T cells are the predominant tumor-infiltrating/tumor-reactive subtype in patients, they have been largely overlooked. We leveraged our autochthonous liver cancer model to analyze TST differentiation and proliferation throughout tumorigenesis. Dual EdU/BrdU labeling studies revealed that throughout tumorigenesis, a subset of TCF1 lo TST in the liver stochastically entered and exited cell cycle, and at later time points there was no evidence of a TCF1 hi progenitor-like population. Moreover, TCF1-knockout TST proliferated and persisted robustly in tumors. Using liver cancer and melanoma models, we showed that tumor-resident TCF1 lo TST proliferate and persist autonomously, even when new TST influx into tumors is inhibited. The prevailing notion is that only TCF1 hi TST self-renew but we now demonstrate, using a clinically relevant mouse cancer model, that TCF1 lo TST stochastically proliferate to achieve long-term population maintenance. Future studies to understand and harness this mechanism to improve T cell persistence in tumors could lead to novel immunotherapies for patients with cancer. SYNOPSIS We show that tumor-specific T cells with little/no expression of TCF1, previously considered incapable of self-renewal, can proliferate stochastically and persist long-term. As TCF1 lo CD8 T cells are often the predominant tumor-reactive T cells found in tumors, future studies should be aimed at reprogramming these proliferating T cells within tumors.