PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1 + CD38 hi cells and anti-PD-1 resistance

Nat Immunol. 2019 Sep;20(9):1231-1243. doi: 10.1038/s41590-019-0441-y. Epub 2019 Jul 29.

Abstract

Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.

Publication types

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

MeSH terms

  • ADP-ribosyl Cyclase 1 / genetics
  • ADP-ribosyl Cyclase 1 / metabolism*
  • Animals
  • Antibodies / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / immunology*
  • Female
  • Humans
  • Immunotherapy / methods
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasms / immunology*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology*
  • Tumor Microenvironment / immunology

Substances

  • Antibodies
  • Cancer Vaccines
  • Membrane Glycoproteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Cd38 protein, mouse
  • ADP-ribosyl Cyclase 1