Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

Nat Commun. 2016 Feb 17:7:10501. doi: 10.1038/ncomms10501.

Abstract

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.

Publication types

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

MeSH terms

  • Adaptive Immunity*
  • Aged
  • Animals
  • B7-H1 Antigen / administration & dosage
  • B7-H1 Antigen / immunology
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Male
  • Mice
  • Middle Aged
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology

Substances

  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus