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

Daniel Sanghoon Shin(University of California, Los Angeles), Jesse M. Zaretsky(University of California, Los Angeles), Helena Escuin-Ordinas(University of California, Los Angeles), Ángel García-Díaz(University of California, Los Angeles), Siwen Hu‐Lieskovan(University of California, Los Angeles), Anusha Kalbasi(University of California, Los Angeles), Catherine S. Grasso(University of California, Los Angeles), Willy Hugo(University of California, Los Angeles), Salemiz Sandoval(University of California, Los Angeles), Davis Y. Torrejon(University of California, Los Angeles), Nicolaos Palaskas(University of California, Los Angeles), Gabriel Abril Rodriguez(University of California, Los Angeles), Giulia Parisi(University of California, Los Angeles), Ariel M. Azhdam(University of California, Los Angeles), Bartosz Chmielowski(University of California, Los Angeles), Grace Cherry(University of California, Los Angeles), Elizabeth Seja(University of California, Los Angeles), Beata Berent-Maoz(University of California, Los Angeles), I. Peter Shintaku(University of California, Los Angeles), Dung T. Le(Sidney Kimmel Comprehensive Cancer Center), Drew M. Pardoll(Sidney Kimmel Comprehensive Cancer Center), Luis A. Díaz(Sidney Kimmel Comprehensive Cancer Center), Paul C. Tumeh(University of California, Los Angeles), Thomas G. Graeber(University of California, Los Angeles), Roger S. Lo(University of California, Los Angeles), Begoña Comı́n-Anduix(University of California, Los Angeles), Antoni Ribas(University of California, Los Angeles)
Cancer Discovery
November 30, 2016
10.1158/2159-8290.cd-16-1223
Cited by 1,284Open Access
Full Text

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.

Related Papers

No related papers found

Powered by citation graph analysis