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.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Shin DS,Zaretsky JM,Escuin-Ordinas H,Garcia-Diaz A,Hu-Lieskovan S,Kalbasi A,Grasso CS,Hugo W,Sandoval S,Torrejon DY,Palaskas N,Rodriguez GA,Parisi G,Azhdam A,Chmielowski B,Cherry G,Seja E,Berent-Maoz B,Shintaku IP,Ldoi
10.1158/2159-8290.CD-16-1223subject
Has Abstractpub_date
2017-02-01 00:00:00pages
188-201issue
2eissn
2159-8274issn
2159-8290pii
2159-8290.CD-16-1223journal_volume
7pub_type
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