Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors

Immunity. 2016 Jun 21;44(6):1255-69. doi: 10.1016/j.immuni.2016.06.001.

Abstract

Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.

Keywords: CTLA-4; PD-1; PD-L1; cancer; immune-checkpoint blockade; immunotherapy; immunotherapy resistance; ipilimumab; microbiome; microbiota.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Costimulatory and Inhibitory T-Cell Receptors / antagonists & inhibitors
  • Costimulatory and Inhibitory T-Cell Receptors / immunology*
  • Drug Resistance, Neoplasm*
  • Humans
  • Immunotherapy / methods*
  • Molecular Targeted Therapy
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Tumor Escape
  • Tumor Microenvironment

Substances

  • Antibodies, Monoclonal
  • Costimulatory and Inhibitory T-Cell Receptors