Journal Article

TCF1 lo CD8 T cells proliferate and persist autonomously in tumors

McDavid, Claudia N, Rudloff, Michael W, Favret, Natalie R, Detrés Román, Carlos R, Wolf, Melissa M, Ewell, Zachary D, Brown, Lincoln A, Roetman, Jessica J, Murray, Kristen A, Erwin, Megan M, Philip, Mary

2026

Overview

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 progeny. This has led to a focus on TCF1 T cells, and though TCF1 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 TST in the liver stochastically entered and exited cell cycle, and at later time points there was no evidence of a TCF1 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 TST proliferate and persist autonomously, even when new TST influx into tumors is inhibited. The prevailing notion is that only TCF1 TST self-renew but we now demonstrate, using a clinically relevant mouse cancer model, that TCF1 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.

• Publisher: Cold Spring Harbor Laboratory Preprints