Therapeutic Interruption of T Cell Development Generates High-Affinity T Cells That Escape Exhaustion and Improve Cancer Immunotherapy

Availability of effective anti-tumor T cells is limited by cancer immunoediting, which depletes neoantigens, and central tolerance, which eliminates developing T cells with high-affinity T cell receptors (TCRs) against tumor self-antigens. Remaining tumor-reactive T cells are often exhausted after immune checkpoint blockade (ICB). Whether endogenous T cells with high- affinity TCRs against tumor self-antigens can be generated to circumvent exhaustion and reject neoantigen-poor tumors is unclear. We show that transiently interrupting central tolerance through RANKL blockade unleashes T cells possessing TCRs with self-reactive features that enable ICB to reject poorly immunogenic tumors. Upon recognition of tumor self-antigens, these T cells exhibit enhanced TCR signaling, enrichment in NFAT/AP-1 genes, and lymph node priming. Consequently, memory-precursor T cells against tumor self-antigens are generated, avoid exhaustion, and become effector-memory cells with transcriptional features associated with clinical ICB response. Thus, interrupting central tolerance provides T cells with tumor- directed autoreactivity that avoid exhaustion and improve immunotherapy.