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

TitleMAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling
Authors
KeywordsSquamous Cell Carcinoma of Head and Neck
Cetuximab
Papillomaviridae
Issue Date2020
PublisherLife Science Alliance LLC. The Journal's web site is located at https://www.life-science-alliance.org/
Citation
Life Science Alliance, 2020, v. 3 n. 4, p. article no. e201900545 How to Cite?
AbstractMAPK 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.
Persistent Identifierhttp://hdl.handle.net/10722/290113
ISSN
2023 Impact Factor: 3.3
2023 SCImago Journal Rankings: 1.907
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorNgan, HL-
dc.contributor.authorLiu, Y-
dc.contributor.authorFong, AY-
dc.contributor.authorPoon, PHY-
dc.contributor.authorYeung, CK-
dc.contributor.authorChan, SSM-
dc.contributor.authorLau, A-
dc.contributor.authorPiao, W-
dc.contributor.authorLi, H-
dc.contributor.authorTse, JSW-
dc.contributor.authorLo, KW-
dc.contributor.authorChan, SM-
dc.contributor.authorSu, YX-
dc.contributor.authorChan, JYK-
dc.contributor.authorLau, CW-
dc.contributor.authorMills, GB-
dc.contributor.authorGrandis, JR-
dc.contributor.authorLui, VWY-
dc.date.accessioned2020-10-22T08:22:17Z-
dc.date.available2020-10-22T08:22:17Z-
dc.date.issued2020-
dc.identifier.citationLife Science Alliance, 2020, v. 3 n. 4, p. article no. e201900545-
dc.identifier.issn2575-1077-
dc.identifier.urihttp://hdl.handle.net/10722/290113-
dc.description.abstractMAPK 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.-
dc.languageeng-
dc.publisherLife Science Alliance LLC. The Journal's web site is located at https://www.life-science-alliance.org/-
dc.relation.ispartofLife Science Alliance-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectSquamous Cell Carcinoma of Head and Neck-
dc.subjectCetuximab-
dc.subjectPapillomaviridae-
dc.titleMAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling-
dc.typeArticle-
dc.identifier.emailSu, YX: richsu@hku.hk-
dc.identifier.authoritySu, YX=rp01916-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.26508/lsa.201900545-
dc.identifier.pmid32381551-
dc.identifier.pmcidPMC7219112-
dc.identifier.scopuseid_2-s2.0-85084398471-
dc.identifier.hkuros316524-
dc.identifier.volume3-
dc.identifier.issue4-
dc.identifier.spagearticle no. e201900545-
dc.identifier.epagearticle no. e201900545-
dc.identifier.isiWOS:000546615600002-
dc.publisher.placeUnited States-
dc.identifier.issnl2575-1077-

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