1. MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling
- Author
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Ngan, Hoi-Lam, Liu, Yuchen, Fong, Andrew Yuon, Poon, Peony Hiu Yan, Yeung, Chun Kit, Chan, Sharon Suet Man, Lau, Alexandria, Piao, Wenying, Li, Hui, Tse, Jessie Sze Wing, Lo, Kwok-Wai, Chan, Sze Man, Su, Yu-Xiong, Chan, Jason Ying Kuen, Lau, Chin Wang, Mills, Gordon B, Grandis, Jennifer Rubin, and Lui, Vivian Wai Yan
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Dental/Oral and Craniofacial Disease ,Genetics ,Cancer ,Rare Diseases ,Good Health and Well Being ,Adult ,Aged ,Aged ,80 and over ,Biomarkers ,Tumor ,Cell Line ,Tumor ,Cohort Studies ,Female ,Gene Regulatory Networks ,Head and Neck Neoplasms ,Humans ,Kaplan-Meier Estimate ,MAP Kinase Signaling System ,Male ,Middle Aged ,Mitogen-Activated Protein Kinases ,Mutation ,Receptor ,ErbB-3 ,Squamous Cell Carcinoma of Head and Neck ,Transcriptome ,Tumor Microenvironment ,Young Adult ,Receptor ,erbB-3 ,Biological sciences ,Biomedical and clinical sciences - Abstract
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.
- Published
- 2020