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

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

Author information

1
University of California, Los Angeles (UCLA), Los Angeles, California.
2
Jonsson Comprehensive Cancer Center, Los Angeles, California.
3
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
4
University of California, Los Angeles (UCLA), Los Angeles, California. aribas@mednet.ucla.edu.

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.

PMID:
27903500
PMCID:
PMC5296316
DOI:
10.1158/2159-8290.CD-16-1223
[Indexed for MEDLINE]
Free PMC Article

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