Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations

Cancer Discov. 2017 Feb;7(2):188-201. doi: 10.1158/2159-8290.CD-16-1223. Epub 2016 Nov 30.

Abstract

Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair-deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.

Significance: A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy. Cancer Discov; 7(2); 188-201. ©2016 AACR.See related commentary by Marabelle et al., p. 128This article is highlighted in the In This Issue feature, p. 115.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal, Humanized / pharmacology
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferon-gamma / pharmacology
  • Janus Kinase 1 / genetics*
  • Janus Kinase 2 / genetics*
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Mutation*
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Signal Transduction / drug effects

Substances

  • Antibodies, Monoclonal, Humanized
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma
  • pembrolizumab
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2