RT Journal Article
SR Electronic
T1 MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900545
DO 10.26508/lsa.201900545
VO 3
IS 6
A1 Ngan, Hoi-Lam
A1 Liu, Yuchen
A1 Fong, Andrew Yuon
A1 Poon, Peony Hiu Yan
A1 Yeung, Chun Kit
A1 Chan, Sharon Suet Man
A1 Lau, Alexandria
A1 Piao, Wenying
A1 Li, Hui
A1 Tse, Jessie Sze Wing
A1 Lo, Kwok-Wai
A1 Chan, Sze Man
A1 Su, Yu-Xiong
A1 Chan, Jason Ying Kuen
A1 Lau, Chin Wang
A1 Mills, Gordon B
A1 Grandis, Jennifer Rubin
A1 Lui, Vivian Wai Yan
YR 2020
UL http://www.life-science-alliance.org/content/3/6/e201900545.abstract
AB 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.