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We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1\/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti\u2013PD-1 therapy in vivo. JAK1\/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti\u2013PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 1079<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-19-1409","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T14:49:31Z","timestamp":1590677371000},"page":"1140-1157","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":153,"title":["Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade"],"prefix":"10.1158","volume":"10","author":[{"given":"Davis Y.","family":"Torrejon","sequence":"first","affiliation":[{"name":"1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, 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California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wohlwender","sequence":"additional","affiliation":[{"name":"4Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8613-0954","authenticated-orcid":false,"given":"Paige","family":"Krystofinski","sequence":"additional","affiliation":[{"name":"1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agustin","family":"Vega-Crespo","sequence":"additional","affiliation":[{"name":"1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher 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