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

  • Author(s): Shin, Daniel Sanghoon
  • Zaretsky, Jesse M
  • Escuin-Ordinas, Helena
  • Garcia-Diaz, Angel
  • Hu-Lieskovan, Siwen
  • Kalbasi, Anusha
  • Grasso, Catherine S
  • Hugo, Willy
  • Sandoval, Salemiz
  • Torrejon, Davis Y
  • Palaskas, Nicolaos
  • Rodriguez, Gabriel Abril
  • Parisi, Giulia
  • Azhdam, Ariel
  • Chmielowski, Bartosz
  • Cherry, Grace
  • Seja, Elizabeth
  • Berent-Maoz, Beata
  • Shintaku, I Peter
  • Le, Dung T
  • Pardoll, Drew M
  • Diaz, Luis A
  • Tumeh, Paul C
  • Graeber, Thomas G
  • Lo, Roger S
  • Comin-Anduix, Begoña
  • Ribas, Antoni
  • et al.
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.

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