Exhausted CD8 T cell progenitors are sustained with TCR engagement during anti-tumor responses

Abstract

Abstract T cell exhaustion is a major contributor to tumor immune invasion. The durability of an anti-tumor response is in part determined by the persistence of exhausted CD8 T cell progenitors (Tpex) that reconstitute the effector T cell pool. While it has been reported that Tpex are able to survive without antigen, the role of TCR engagement in regulating Tpex self-renewal during tumor progression remains to be fully explored. Here, we used a Lewis lung carcinoma model where a robust or dampened TCR signal was elicited resulting in bona fide tumor-infiltrating Tpex. Longitudinal analysis of tumor-specific CD8 T cells revealed that robust TCR stimulation was required for the formation and maintenance of the Tpex reservoir in tumor-draining lymph nodes (tdLNs). Replenishment of tumor-infiltrating Tpex was abrogated by suboptimal priming despite a generation of central memory-like T cells in tdLNs. Moreover, attenuated TCR engagement substantially accelerated the terminal differentiation of optimally primed Tpex. Chromatin accessibility and whole genome DNA methylation profiling revealed that Tpex-associated epigenetic programs were significantly enriched in optimally engaged T cells in tdLNs. Additionally, tumor-infiltrating sub-primed Tpex gained more Ets1 motifs while Tpex established from robust TCR stimulation acquired greater chromatin accessibility at Tcf-1 targeting loci. These Tcf-1 targets were further validated to be Tpex-specific when compared to those in naive T cells. Collectively, our results highlight the importance of TCR engagement in sustaining Tpex during tumor progression.