Subsets of exhausted CD8 + T cells differentially mediate tumor control and respond to checkpoint blockade

Nat Immunol. 2019 Mar;20(3):326-336. doi: 10.1038/s41590-019-0312-6. Epub 2019 Feb 18.

Abstract

T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+ TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8+ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+ T cells might be an important component of improving the response to checkpoint blockade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / immunology
  • Antibodies, Blocking / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Line, Tumor
  • Female
  • Humans
  • Lymphocyte Subsets / drug effects
  • Lymphocyte Subsets / immunology
  • Lymphocyte Subsets / virology
  • Lymphocytes, Tumor-Infiltrating / drug effects*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / virology
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / prevention & control
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / drug effects
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / physiology
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / prevention & control*
  • Melanoma, Experimental / virology
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism

Substances

  • Antibodies, Blocking
  • Programmed Cell Death 1 Receptor