The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8+ T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8+ T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8+ T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8+ cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (TTSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-TTSM cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-TTSM cells could be harnessed to potentiate anti-tumor immunotherapy. [Display omitted] •TdLN-TTSM cells are bona fide memory T cells•Exhaustion-associated epigenetic scaring marks TPEX but not TdLN-TTSM cells•Adoptive transfer of TdLN-TTSM represents a promising immunotherapy strategy•TdLN-TTSM cells are primary responders to PD-1/PD-L1 ICB Huang et al. demonstrate different functional states of tumor-reactive CD8+ T cells in the TdLNs where TCF-1+TOX− CD8+ T cells are bona fide memory T cells and function as the genuine responders to PD-1/PD-L1 ICB.