{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:05:16Z","timestamp":1789542316597,"version":"build-2803163510"},"reference-count":50,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"unspecified","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["5P20GM121322"],"award-info":[{"award-number":["5P20GM121322"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-10-1-0203"],"award-info":[{"award-number":["W81XWH-10-1-0203"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P50 CA94056"],"award-info":[{"award-number":["P50 CA94056"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,1,12]]},"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The presence of a highly immunosuppressive tumor microenvironment has limited the success of immune checkpoint therapy (ICT). Immune suppressing myeloid cells with increased production of reactive oxygen species are critical drivers of this immunosuppressive tumor microenvironment. Strategies to limit these immune suppressing myeloid cells are needed to enhance response to ICT.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>To evaluate the contribution of myeloperoxidase (MPO), a myeloid lineage-restricted enzyme and a major source of reactive oxygen species, to mediating ICT response, we compared treatment outcome and immune composition in wild-type, MPO-deficient (<jats:italic>MPO<\/jats:italic>\n                     <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                     <\/jats:sup>), and MPO inhibitor-treated wild-type mice using established primary melanoma models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Tumor growth and survival studies demonstrated that either host deficiency (<jats:italic>MPO<\/jats:italic>\n                     <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                     <\/jats:sup>) or pharmacological inhibition of MPO enhanced ICT response in two preclinical models of established primary melanoma in aged animals. The tumor microenvironment and systemic immune landscape underwent striking changes in infiltration of myeloid cells, T cells, B cells, and dendritic cells in <jats:italic>MPO<\/jats:italic>\n                     <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                     <\/jats:sup> mice; furthermore, a significant increase in myeloid cells was observed in ICT non-responders. The contribution of CD4<jats:sup>+<\/jats:sup> T cells and NK cells during ICT response also changed in <jats:italic>MPO<\/jats:italic>\n                     <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                     <\/jats:sup> mice. Interestingly, MPO enzymatic activity, but not protein, was increased in CD11b<jats:sup>+<\/jats:sup>Ly6G<jats:sup>+<\/jats:sup> myeloid cells isolated from marrow, spleen, and peritoneal cavities of mice bearing untreated melanoma, indicating systemic activation of innate immunity. Notably, repurposing MPO-specific inhibitors (verdiperstat, AZD5904) in combination with ICT pointedly enhanced response rates above ICT alone. Indeed, long-term survival was 100% in the YUMM3.3 melanoma model on treatment with verdiperstat plus ICT.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>MPO contributes to ICT resistance in established melanoma. Repurposing MPO-specific inhibitors may provide a promising therapeutic strategy to enhance ICT response.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-005837","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T09:55:17Z","timestamp":1676627717000},"page":"e005837","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0671-8390","authenticated-orcid":false,"given":"Tracy W","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"},{"name":"Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8647-0975","authenticated-orcid":false,"given":"Seth T","family":"Gammon","sequence":"additional","affiliation":[{"name":"Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencai","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2120-7217","authenticated-orcid":false,"given":"David","family":"Piwnica-Worms","sequence":"additional","affiliation":[{"name":"Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"key":"2025100306523902000_11.2.e005837.1","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2021.39.15_suppl.9506","article-title":"CheckMate 067: 6.5-year outcomes in patients (PTS) with advanced melanoma","volume":"39","author":"Wolchok","year":"2021","journal-title":"JCO"},{"key":"2025100306523902000_11.2.e005837.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836"},{"key":"2025100306523902000_11.2.e005837.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709684"},{"key":"2025100306523902000_11.2.e005837.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1302369"},{"key":"2025100306523902000_11.2.e005837.5","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1056\/NEJMc1714339","article-title":"Nivolumab and ipilimumab in advanced melanoma","volume":"377","author":"Alegre-del-Rey","year":"2017","journal-title":"N Engl J Med"},{"key":"2025100306523902000_11.2.e005837.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-013-1508-5"},{"key":"2025100306523902000_11.2.e005837.7","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/CMR.0000000000000515","article-title":"Innate immune cell infiltration in melanoma metastases affects survival and is associated with BRAFV600E mutation status","volume":"29","author":"Dabrosin","year":"2019","journal-title":"Melanoma Res"},{"key":"2025100306523902000_11.2.e005837.8","doi-asserted-by":"crossref","unstructured":"Gondois-Rey F , Paul M , Alcaraz F , et al . 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