RT Journal Article SR Electronic T1 MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201900545 DO 10.26508/lsa.201900545 VO 3 IS 6 A1 Ngan, Hoi-Lam A1 Liu, Yuchen A1 Fong, Andrew Yuon A1 Poon, Peony Hiu Yan A1 Yeung, Chun Kit A1 Chan, Sharon Suet Man A1 Lau, Alexandria A1 Piao, Wenying A1 Li, Hui A1 Tse, Jessie Sze Wing A1 Lo, Kwok-Wai A1 Chan, Sze Man A1 Su, Yu-Xiong A1 Chan, Jason Ying Kuen A1 Lau, Chin Wang A1 Mills, Gordon B A1 Grandis, Jennifer Rubin A1 Lui, Vivian Wai Yan YR 2020 UL http://www.life-science-alliance.org/content/3/6/e201900545.abstract AB 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 TP53 mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) 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 “CD8+ T-cell–inflamed” tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3–4 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.