Journal
CANCER DISCOVERY
Volume 7, Issue 2, Pages 188-201Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-16-1223
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Funding
- NIH [R35 CA197633, P01 CA168585, GM08042]
- Parker Institute for Cancer Immunotherapy (PICI)
- Dr. Robert Vigen Memorial Fund
- Ruby Family Fund
- Garcia-Corsini Family Fund
- Ressler Family Fund
- Samuels Family Fund
- Grimaldi Family Fund
- Oncology training grants [5T32CA009297-30]
- Dermatology training grants [5T32AR058921-05]
- Tumor Immunology training grants [5T32CA009120-39, 4T32CA009120-40]
- Conquer Cancer Foundation ASCO Young Investigator Award
- Tower Cancer Research Foundation Grant
- Stand Up To Cancer - Cancer Research Institute Cancer Immunology Dream Team Translational Research Grant [SU2C-AACR-DT1012]
- Conquer Cancer Foundation ASCO Career Development Award
- Tower Cancer Foundation Research Grant
- V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research
- Division of Medical Oncology and Immunotherapy (University Hospital of Siena)
- American Cancer Society Research Scholar Award [RSG-12-257-01-TBE]
- Melanoma Research Alliance Established Investigator Award [20120279]
- National Center for Advancing Translational Sciences UCLA CTSI Grant [UL1TR000124]
- Steven C. Gordon Family Foundation
- Wade F.B. Thompson/Cancer Research Institute CLIP Grant
- Swim Across America Laboratory
- Commonwealth Fund at Johns Hopkins
- Milstein Research Scholar Award from the American Skin Association
- AACR-Amgen, Inc. [6-40-11-HUGO]
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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 repairdefi cient 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. (C) 2017 AACR.
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