Tumor immunogenicity dictates reliance on TCF1 in CD8+ T cells for response to immunotherapy

Abstract

Stem-like CD8+ Tcells are regulated by Tcell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1+CD8+ Tcells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8+ Tcells and ICB response in poorly immunogenic tumors that accumulate TOX+ dysfunctional Tcells, but is dispensable for Tcell priming and therapy response in highly immunogenic tumors that efficiently expand transitory effectors. Importantly, improving Tcell priming by vaccination or by enhancing antigen presentation on tumors rescues the defective responses of TCF1-deficient CD8+ Tcells upon ICB in poorly immunogenic tumors. Our study highlights TCF1's role during the early stages of anti-tumor CD8+ Tcell responses with important implications for guiding optimal therapeutic interventions in cancers with low TCF1+CD8+ Tcells and low-neo-antigen expression.