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

Abstract

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 (T_TSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-T_TSM 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-T_TSM cells could be harnessed to potentiate anti-tumor immunotherapy.