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 -reac-tive 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 high-light 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 find-ings highlight that TdLN-TTSM cells could be harnessed to potentiate anti-tumor immunotherapy.