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

Cell. 2022 Oct 27;185(22):4049-4066.e25. doi: 10.1016/j.cell.2022.09.020. Epub 2022 Oct 7.


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.

Keywords: draining lymph nodes; exhaustion; immune-checkpoint blockade; memory CD8(+) T cells; tumor-specific CD8(+) T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen*
  • CD8-Positive T-Lymphocytes
  • Humans
  • Immune Checkpoint Inhibitors
  • Lymph Nodes / pathology
  • Neoplasms* / pathology
  • Neoplasms* / therapy
  • Programmed Cell Death 1 Receptor
  • Tumor Microenvironment


  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor
  • Immune Checkpoint Inhibitors