Intratumoral Tcf1PD-1CD8 T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy.

Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8 T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal differentiation or exhaustion of tumor-specific T cells. Here we identified a subset of tumor-reactive TILs bearing hallmarks of exhausted cells and central memory cells, including expression of the checkpoint protein PD-1 and the transcription factor Tcf1. Tcf1PD-1 TILs mediated the proliferative response to immunotherapy, generating both Tcf1PD-1 and differentiated Tcf1PD-1 cells. Ablation of Tcf1PD-1 TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1PD-1 TILs but was essential for the stem-like functions of these cells. Human TCF1PD-1 cells were detected among tumor-reactive CD8 T cells in the blood of melanoma patients and among TILs of primary melanomas. Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.