Hallmarks of CD8 T cell dysfunction are established within hours of tumor antigen encounter prior to cell division

Abstract Tumor-specific CD8 T cells (TST) found in patients with cancer are dysfunctional and unable to halt cancer progressions. TST dysfunction, also known as T cell exhaustion, is thought to be driven by chronic T cell receptor/antigen stimulation and immunosuppressive factors within the tumor microenvironment. However, we know little about the interplay between CD8 T cell function, cell division, and epigenetic remodeling during the first hours following activation and tumor encounter. Here, we assessed TST differentiation, cell division, chromatin accessibility, and transcription in two clinically-relevant cancer mouse models (autochthonous liver cancer and metastatic melanoma), and we compared TST fate trajectories to those of CD8 T cells differentiating during acute infection. Surprisingly, despite robust activation and proliferation, TST had near complete effector function impairment even prior to undergoing cell division, and had acquired hallmark chromatin accessibility features previously observed in late dysfunctional/exhausted T cells. Moreover, continued tumor/antigen exposure drove progressive epigenetic remodeling, “imprinting” the dysfunctional state. Our study defines for the first time the regulation and kinetics underlying T cell fate choice prior to cell division in the context of tumors versus infection. Citation Format: Mary Philip, Michael W. Rudloff, Paul Zumbo, Doron Betel, Natalie R. Favret, Jessica J. Roetman, Carlos R. Detres Roman, Megan M. Erwin, Kristen A. Murray, Sriya T. Jonnakuti, Friederike Dundar. Hallmarks of CD8 T cell dysfunction are established within hours of tumor antigen encounter prior to cell division [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr PR06.