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Alliance"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:p>MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with <jats:italic>TP53<\/jats:italic> mutations (median \u223c14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (<jats:italic>A\/BRAF<\/jats:italic>, <jats:italic>HRAS<\/jats:italic>, <jats:italic>MAPK1<\/jats:italic>, and <jats:italic>MAP2K1\/2<\/jats:italic>) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only \u201cCD8<jats:sup>+<\/jats:sup> T-cell\u2013inflamed\u201d tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8<jats:sup>+<\/jats:sup> T-cell recruitment in situ. Consistent with CD8<jats:sup>+<\/jats:sup> T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3\u20134 times longer than WT patients with anti-PD1\/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.<\/jats:p>","DOI":"10.26508\/lsa.201900545","type":"journal-article","created":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T23:01:26Z","timestamp":1588892486000},"page":"e201900545","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling"],"prefix":"10.26508","volume":"3","author":[{"given":"Hoi-Lam","family":"Ngan","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7647-6481","authenticated-orcid":true,"given":"Yuchen","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew Yuon","family":"Fong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peony Hiu Yan","family":"Poon","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Kit","family":"Yeung","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of 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