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

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