Hallmark features of T cell dysfunction are established within hours after tumor antigen encounter

• Published in: The Journal of immunology (1950) 2022-05, Vol.208 (1_Supplement), p.121-121.08
• Main Authors: Rudloff, Michael William, Favret, Natalie, Zumbo, Paul, Dündar, Friederike, Betel, Doron, Philip, Mary
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.208.Supp.121.08

Tumor-specific CD8 T cells (TST) found in patients with cancer are dysfunctional and unable to halt cancer progression. TST dysfunction, also known as exhaustion, is encoded by specific epigenetic and transcriptional programs and thought to be induced by chronic antigen stimulation. Using a genetic liver cancer mouse model, we followed the fate of naïve TST in tumor-bearing hosts. Strikingly, we found that within hours after encountering tumor antigen, TST lost effector function, expressed high levels of inhibitory receptors, and displayed chromatin peak accessibility changes previously characterized in late-stage dysfunction. This rapid onset challenges the paradigm that chronic antigen/T cell receptor stimulation is required to induce dysfunction/exhaustion. Moreover, dysfunction-associated epigenetic features were established even prior to cell division, opposing the prevailing notion that cell divisions are required for epigenetic remodeling and T cell differentiation. To determine whether these early dysfunction hallmarks were “imprinted”, we reisolated TST from malignant lesions and transferred them into antigen-free hosts. While loss of effector function was imprinted within hours of tumor exposure, other dysfunctional hallmarks, including PD1 expression, required several days of tumor exposure and additional chromatin remodeling to become stably encoded. Our study reveals the rapid induction and epigenetic remodeling which underlies TST commitment to the dysfunctional fate, highlighting the need to target early activation-induced pathways to improve anti-cancer T cell immunity. Supported by T32GM007347-43