{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T03:27:44Z","timestamp":1793417264964,"version":"4.5.0"},"reference-count":47,"publisher":"American Association for Cancer Research (AACR)","issue":"2","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2013PD-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\u2013deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti\u2013PD-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.<\/jats:p>\n                  <jats:p>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\u2013201. \u00a92016 AACR.<\/jats:p>\n                  <jats:p>See related commentary by Marabelle et al., p. 128.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 115<\/jats:p>","DOI":"10.1158\/2159-8290.cd-16-1223","type":"journal-article","created":{"date-parts":[[2016,11,30]],"date-time":"2016-11-30T22:50:32Z","timestamp":1480546232000},"page":"188-201","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":1285,"title":["Primary Resistance to PD-1 Blockade Mediated by\n                    <i>JAK1\/2<\/i>\n                    Mutations"],"prefix":"10.1158","volume":"7","author":[{"given":"Daniel Sanghoon","family":"Shin","sequence":"first","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse M.","family":"Zaretsky","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Escuin-Ordinas","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Garcia-Diaz","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwen","family":"Hu-Lieskovan","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusha","family":"Kalbasi","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine S.","family":"Grasso","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willy","family":"Hugo","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salemiz","family":"Sandoval","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davis Y.","family":"Torrejon","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolaos","family":"Palaskas","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Abril","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Parisi","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Azhdam","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartosz","family":"Chmielowski","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."},{"name":"2Jonsson Comprehensive Cancer Center, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Cherry","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Seja","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Berent-Maoz","sequence":"additional","affiliation":[{"name":"1University of California, Los Angeles (UCLA), Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. 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