Paper

TCF1lo CD8 T cells proliferate and persist autonomously in tumors

Rudloff, Michael W, Favret, Natalie R, Wolf, Melissa, Mcdavid, Claudia, Ewell, Zachary D, Brown, Lincoln A, Roetman, Jessica J, Murray, Kristen A, Erwin, Megan M, Philip, Mary, Detres Roman, Carlos R

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 TCF1lo progeny. This has led to a focus on TCF1hi T cells, and though TCF1lo 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 TCF1lo TST in the liver stochastically entered and exited cell cycle, and at later time points there was no evidence of a TCF1hi progenitor-like population. Moreover, TCF1-knockout TST proliferated and persisted robustly in tumors. Using liver cancer and melanoma models, we showed that tumor-resident TCF1lo TST proliferate and persist autonomously, even when new TST influx into tumors is inhibited. The prevailing notion is that only TCF1hi TST self-renew but we now demonstrate, using a clinically relevant mouse cancer model, that TCF1lo 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.Competing Interest StatementThe authors have declared no competing interest.Funder Information DeclaredNational Institute of Arthritis and Musculoskeletal and Skin Diseases, T32AR059039National Institute of General Medical Sciences, https://ror.org/04q48ey07, T32GM008554, T32GM007347American Society of Hematology, https://ror.org/02nw48b86, ASH Medical Student Physician-Scientist AwardV Foundation, V Foundation Scholar AwardNational Institute of Diabetes and Digestive and Kidney Diseases, https://ror.org/00adh9b73, P30DK058404National Cancer Institute, T32CA009592, R37CA263614, P30CA068485

• Publisher: Cold Spring Harbor Laboratory Press
• Subject: CD8 antigen / Cell cycle / Cell self-renewal / Chronic infection / Diabetes mellitus / Hematology / Hepatocyte nuclear factor 1 / Immunotherapy / Kidney diseases / Liver cancer / Lymphocytes / Lymphocytes T / Melanoma / Population dynamics / Population studies / Progenitor cells / Skin diseases / Tumorigenesis / Tumors