Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Nat Commun. 2017 Oct 26;8(1):1136. doi: 10.1038/s41467-017-01062-w.


Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antigen Presentation / drug effects*
  • Antigen Presentation / genetics
  • CTLA-4 Antigen / immunology
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Loss of Heterozygosity
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Metastasis
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Point Mutation
  • Programmed Cell Death 1 Receptor / immunology
  • beta 2-Microglobulin / genetics


  • Antibodies, Monoclonal
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Programmed Cell Death 1 Receptor
  • beta 2-Microglobulin