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With these therapies, we now face new mechanisms of tumor-acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T-cell transfer therapy (ACT) to the MART1 antigen, a phenomenon that had been observed only in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART1 T cell receptor\u2013expressing T cells or with TNF\u03b1, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.<\/jats:p>\n                  <jats:p>Significance: We report a patient whose metastatic melanoma underwent inflammation-induced dedifferentiation as a resistance mechanism to ACT to the MART1 antigen. Our results suggest that future melanoma ACT protocols may benefit from the simultaneous targeting of multiple tumor antigens, modulating the inflammatory response, and inhibition of inflammatory dedifferentiation-inducing signals. Cancer Discov; 8(8); 935\u201343. \u00a92018 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 899<\/jats:p>","DOI":"10.1158\/2159-8290.cd-17-1178","type":"journal-article","created":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T10:31:49Z","timestamp":1529058709000},"page":"935-943","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":187,"title":["Immunotherapy Resistance by Inflammation-Induced Dedifferentiation"],"prefix":"10.1158","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0313-2848","authenticated-orcid":false,"given":"Arnav","family":"Mehta","sequence":"first","affiliation":[{"name":"1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California."},{"name":"2Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon Joo","family":"Kim","sequence":"additional","affiliation":[{"name":"1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Robert","sequence":"additional","affiliation":[{"name":"1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Tsoi","sequence":"additional","affiliation":[{"name":"1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bego\u00f1a","family":"Comin-Anduix","sequence":"additional","affiliation":[{"name":"3Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California."},{"name":"4Johnson Comprehensive Cancer Center, University of California, Los Angeles, 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