PTPN2 regulates the generation of exhausted CD8 + T cell subpopulations and restrains tumor immunity

Nat Immunol. 2019 Oct;20(10):1335-1347. doi: 10.1038/s41590-019-0480-4. Epub 2019 Sep 16.

Abstract

CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+ cells without altering Slamf6+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8+ T cells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology*
  • Animals
  • CD8-Positive T-Lymphocytes / physiology*
  • Cellular Senescence
  • Colonic Neoplasms / immunology*
  • Cytotoxicity, Immunologic
  • Female
  • Hepatitis A Virus Cellular Receptor 2 / metabolism
  • Immune Tolerance
  • Immunotherapy / methods*
  • Interferon Type I / metabolism
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / physiology*
  • Lymphoid Progenitor Cells / physiology*
  • Male
  • Melanoma / immunology*
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism*
  • Signal Transduction
  • Signaling Lymphocytic Activation Molecule Family / metabolism
  • Skin Neoplasms / immunology*

Substances

  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Interferon Type I
  • Signaling Lymphocytic Activation Molecule Family
  • Slamf6 protein, mouse
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Ptpn2 protein, mouse