{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:05:22Z","timestamp":1790712322665,"version":"4.1.0"},"reference-count":26,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["RO1CA169134,PO1CA114046,PO1CA165997,P30CA016520,P50CA174523,RO1CA198015"],"award-info":[{"award-number":["RO1CA169134,PO1CA114046,PO1CA165997,P30CA016520,P50CA174523,RO1CA198015"]}]},{"DOI":"10.13039\/100006920","name":"University of Pennsylvania","doi-asserted-by":"crossref","award":["Penn-Incyte Alliance grant"],"award-info":[{"award-number":["Penn-Incyte Alliance grant"]}],"id":[{"id":"10.13039\/100006920","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006920","name":"University of Pennsylvania","doi-asserted-by":"crossref","award":["Tara Miller Research Center grant"],"award-info":[{"award-number":["Tara Miller Research Center grant"]}],"id":[{"id":"10.13039\/100006920","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,3]]},"abstract":"<jats:p>\n                    New strategies are needed to enhance the efficacy of anti\u2013programmed cell death protein antibody (anti\u2013PD-1 Ab) in cancer. Here, we report that inhibiting palmitoyl-protein thioesterase 1 (PPT1), a target of chloroquine derivatives like hydroxychloroquine (HCQ), enhances the antitumor efficacy of anti\u2013PD-1 Ab in melanoma. The combination resulted in tumor growth impairment and improved survival in mouse models. Genetic suppression of core autophagy genes, but not\n                    <jats:italic>Ppt1<\/jats:italic>\n                    , in cancer cells reduced priming and cytotoxic capacity of primed T cells. Exposure of antigen-primed T cells to macrophage-conditioned medium derived from macrophages treated with PPT1 inhibitors enhanced melanoma-specific killing. Genetic or chemical Ppt1 inhibition resulted in M2 to M1 phenotype switching in macrophages. The combination was associated with a reduction in myeloid-derived suppressor cells in the tumor. Ppt1 inhibition by HCQ, or DC661, induced cyclic GMP-AMP synthase\/stimulator of interferon genes\/TANK binding kinase 1 pathway activation and the secretion of interferon-\u03b2 in macrophages, the latter being a key component for augmented T cell\u2013mediated cytotoxicity. Genetic\n                    <jats:italic>Ppt1<\/jats:italic>\n                    inhibition produced similar findings. These data provide the rationale for this combination in melanoma clinical trials and further investigation in other cancers.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.133225","type":"journal-article","created":{"date-parts":[[2020,8,11]],"date-time":"2020-08-11T12:07:24Z","timestamp":1597147644000},"source":"Crossref","is-referenced-by-count":82,"title":["PPT1 inhibition enhances the antitumor activity of anti\u2013PD-1 antibody in melanoma"],"prefix":"10.1172","volume":"5","author":[{"given":"Gaurav","family":"Sharma","sequence":"first","affiliation":[{"name":"Abramson Cancer Center and Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rani","family":"Ojha","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center and Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6507-0673","authenticated-orcid":true,"given":"Estela","family":"Noguera-Ortega","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center and Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito W.","family":"Rebecca","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center and Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Attanasio","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics and Penn Institute for Immunology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengfu","family":"Piao","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center and Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center and Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6283-5543","authenticated-orcid":true,"given":"Michael C.","family":"Nicastri","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts & Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra L.","family":"Harper","sequence":"additional","affiliation":[{"name":"Wistar Institute, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amruta","family":"Ronghe","sequence":"additional","affiliation":[{"name":"Wistar Institute, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9235-6236","authenticated-orcid":true,"given":"Vaibhav","family":"Jain","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center and Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Winkler","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts & Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Speicher","sequence":"additional","affiliation":[{"name":"Wistar Institute, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Mastio","sequence":"additional","affiliation":[{"name":"Wistar Institute, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phyllis A.","family":"Gimotty","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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