PT - JOURNAL ARTICLE AU - Ngan, Hoi-Lam AU - Liu, Yuchen AU - Fong, Andrew Yuon AU - Poon, Peony Hiu Yan AU - Yeung, Chun Kit AU - Chan, Sharon Suet Man AU - Lau, Alexandria AU - Piao, Wenying AU - Li, Hui AU - Tse, Jessie Sze Wing AU - Lo, Kwok-Wai AU - Chan, Sze Man AU - Su, Yu-Xiong AU - Chan, Jason Ying Kuen AU - Lau, Chin Wang AU - Mills, Gordon B AU - Grandis, Jennifer Rubin AU - Lui, Vivian Wai Yan TI - MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling AID - 10.26508/lsa.201900545 DP - 2020 Jun 01 TA - Life Science Alliance PG - e201900545 VI - 3 IP - 6 4099 - http://www.life-science-alliance.org/content/3/6/e201900545.short 4100 - http://www.life-science-alliance.org/content/3/6/e201900545.full SO - Life Sci. Alliance2020 Jun 01; 3 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.