MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling
Publication in refereed journal


摘要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.
著者Hoi-Lam NGAN, Yuchen LIU, Andrew Yuon FONG, Peony Hiu Yan POON, Chun Kit YEUNG, Sharon Suet Man CHAN, Alexandria LAU, Wenying PIAO, Hui LI, Jessie Sze Wing TSE, Kwok-Wai LO, Sze Man CHAN, Yu-Xiong SU, Jason Ying Kuen CHAN, Chin Wang LAU, Gordon B MILLS, Jennifer Rubin GRANDIS, Vivian Wai Yan LUI
期刊名稱Life Science Alliance
出版社Life Science Alliance

上次更新時間 2021-10-10 於 23:27