{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:03:01Z","timestamp":1791820981702,"version":"4.3.4"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["ZIA-DC00008, Z01-DC-00016, Z01-DC-00073, Z01-DC-00074"],"award-info":[{"award-number":["ZIA-DC00008, Z01-DC-00016, Z01-DC-00073, Z01-DC-00074"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006229","name":"Oak Ridge Institute for Science and Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006229","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Amplification of human chromosome 3q26-29, which encodes oncoprotein \u0394Np63 among other isoforms of the p63 family, is a feature common to squamous cell carcinomas (SCCs) of multiple tissue origins. Along with overexpression of \u0394Np63, activation of the protooncogene, <jats:italic>RAS<\/jats:italic>, whether by overexpression or oncogenic mutation, is frequently observed in many cancers. In this study, analysis of transcriptome data from The Cancer Genome Atlas (TCGA) demonstrated that expression of <jats:italic>TP63 mRNA<\/jats:italic>, particularly <jats:italic>\u0394Np63<\/jats:italic> isoforms, and <jats:italic>HRAS<\/jats:italic> are significantly elevated in advanced squamous cell carcinomas of the head and neck (HNSCCs), suggesting pathological significance. However, how co-overexpressed \u0394Np63 and HRAS affect the immunosuppressive tumor microenvironment (TME) is incompletely understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we established and characterized an immune competent mouse model using primary keratinocytes with retroviral-mediated overexpression of \u0394Np63\u03b1 and constitutively activated HRAS (v-ras<jats:sup>Ha<\/jats:sup> G12R) to evaluate the role of these oncogenes in the immune TME.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this model, orthotopic grafting of wildtype syngeneic keratinocytes expressing both v-ras<jats:sup>Ha<\/jats:sup> and elevated levels of \u0394Np63\u03b1 consistently yield carcinomas in syngeneic hosts, while cells expressing v-ras<jats:sup>Ha<\/jats:sup> alone yield predominantly papillomas. We found that polymorphonuclear (PMN) myeloid cells, experimentally validated to be immunosuppressive and thus representing myeloid-derived suppressor cells (PMN-MDSCs), were significantly recruited into the TME of carcinomas arising early following orthotopic grafting of \u0394Np63\u03b1\/v-ras<jats:sup>Ha<\/jats:sup>-expressing keratinocytes. \u0394Np63\u03b1\/v-ras<jats:sup>Ha<\/jats:sup>-driven carcinomas expressed higher levels of chemokines implicated in recruitment of MDSCs compared to v-ras<jats:sup>Ha<\/jats:sup>-initiated tumors, providing a heretofore undescribed link between \u0394Np63\u03b1\/HRAS-driven carcinomas and the development of an immunosuppressive TME.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results support the utilization of a genetic carcinogenesis model harboring specific genomic drivers of malignancy to study mechanisms underlying the development of local immunosuppression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1200970","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T23:10:41Z","timestamp":1691709041000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Oncogenic Ras and \u0394Np63\u03b1 cooperate to recruit immunosuppressive polymorphonuclear myeloid-derived suppressor cells in a mouse model of squamous cancer pathogenesis"],"prefix":"10.3389","volume":"14","author":[{"given":"Nozomi","family":"Sakakibara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pa\u00fal E.","family":"Clavijo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cem","family":"Sievers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica 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