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

AI Article Synopsis

  • * These mutations disrupt the ErbB3 activation, which is known to drive HNSCC progression, and are associated with high levels of CD8 T-cell inflammation in tumors, leading to better immune responses.
  • * MAPK-mutant HNSCC patients respond better to immunotherapies like anti-PD1/PD-L1, showing 3.3-4 times longer survival compared to wild-type patients, highlighting the potential for using these mutations as biomarkers for predicting favorable outcomes.

Article 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 mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (, , , and ) 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219112PMC
http://dx.doi.org/10.26508/lsa.201900545DOI Listing

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