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MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling.

  • Author(s): 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;
  • Lui, Vivian Wai Yan
  • et al.
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.

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