Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy

Immunity. 2019 Jan 15;50(1):195-211.e10. doi: 10.1016/j.immuni.2018.12.021. Epub 2019 Jan 8.


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. Tcf1+PD-1+ TILs mediated the proliferative response to immunotherapy, generating both Tcf1+PD-1+ and differentiated Tcf1-PD-1+ cells. Ablation of Tcf1+PD-1+ TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1+PD-1+ TILs but was essential for the stem-like functions of these cells. Human TCF1+PD-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.

Keywords: T cell exhaustion; T cell factor 1; T cell reinvigoration; cancer immunotherapy; checkpoint blockade; memory-like T cells; stem-like T cells; therapeutic vaccination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation
  • Cell Proliferation
  • Hepatitis A Virus Cellular Receptor 2 / antagonists & inhibitors
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Humans
  • Immunotherapy
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Melanoma / immunology
  • Melanoma / therapy*
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Stem Cells / immunology*
  • T-Lymphocyte Subsets / immunology*


  • Antibodies, Monoclonal
  • HAVCR2 protein, human
  • HNF1A protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Hepatocyte Nuclear Factor 1-alpha
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor