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EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma

Eph receptors constitute the largest family of RTKs, and their associations with antitumor immunity and immunotherapy are largely unknown. By integrating genomic, transcriptomic and clinical data from cohorts in public databases, we identified EPHA5 as the most common mutated gene of Eph receptors i...

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Autores principales: Chen, Zhiming, Chen, Ji, Ren, Dandan, Zhang, Jiao, Yang, Ying, Zhang, Henghui, Mao, Beibei, Ma, Haitao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834994/
https://www.ncbi.nlm.nih.gov/pubmed/33288738
http://dx.doi.org/10.18632/aging.202169
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author Chen, Zhiming
Chen, Ji
Ren, Dandan
Zhang, Jiao
Yang, Ying
Zhang, Henghui
Mao, Beibei
Ma, Haitao
author_facet Chen, Zhiming
Chen, Ji
Ren, Dandan
Zhang, Jiao
Yang, Ying
Zhang, Henghui
Mao, Beibei
Ma, Haitao
author_sort Chen, Zhiming
collection PubMed
description Eph receptors constitute the largest family of RTKs, and their associations with antitumor immunity and immunotherapy are largely unknown. By integrating genomic, transcriptomic and clinical data from cohorts in public databases, we identified EPHA5 as the most common mutated gene of Eph receptors in lung adenocarcinoma (LUAD). Moreover, compared with EPHA5 wild-type (WT) patients, EPHA5-mutant (Mut) patients exhibited significantly enhanced infiltration of CD8(+) T cells and M1 macrophages, reduced recruitment of immunosuppressive regulatory T cells (Tregs) into the tumor site, as well as the increased level of chemokine, interferon-gamma, inhibitory immune checkpoint signatures, tumor mutation burden (TMB) and tumor neoantigen burden (TNB). Additionally, EPHA5 mutation cooccurred with homologous recombination (HR) or mismatch repair (MMR) gene mutations. These data were validated in the LUAD cell line H1299 and a Chinese LUAD cohort. Most importantly, clinical analysis of a Memorial Sloan Kettering Cancer Center (MSKCC) immunotherapy cohort indicated that LUAD patients with EPHA5 mutations who were treated with immunotherapy had markedly prolonged survival times. Our results revealed the correlation of EPHA5 mutations with tumor immune microenvironment and predictive factors for immunotherapy, implying the potential of EPHA5 mutations as a prognostic marker for the prognosis of LUAD patients to immune checkpoint blockade therapy.
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spelling pubmed-78349942021-02-03 EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma Chen, Zhiming Chen, Ji Ren, Dandan Zhang, Jiao Yang, Ying Zhang, Henghui Mao, Beibei Ma, Haitao Aging (Albany NY) Research Paper Eph receptors constitute the largest family of RTKs, and their associations with antitumor immunity and immunotherapy are largely unknown. By integrating genomic, transcriptomic and clinical data from cohorts in public databases, we identified EPHA5 as the most common mutated gene of Eph receptors in lung adenocarcinoma (LUAD). Moreover, compared with EPHA5 wild-type (WT) patients, EPHA5-mutant (Mut) patients exhibited significantly enhanced infiltration of CD8(+) T cells and M1 macrophages, reduced recruitment of immunosuppressive regulatory T cells (Tregs) into the tumor site, as well as the increased level of chemokine, interferon-gamma, inhibitory immune checkpoint signatures, tumor mutation burden (TMB) and tumor neoantigen burden (TNB). Additionally, EPHA5 mutation cooccurred with homologous recombination (HR) or mismatch repair (MMR) gene mutations. These data were validated in the LUAD cell line H1299 and a Chinese LUAD cohort. Most importantly, clinical analysis of a Memorial Sloan Kettering Cancer Center (MSKCC) immunotherapy cohort indicated that LUAD patients with EPHA5 mutations who were treated with immunotherapy had markedly prolonged survival times. Our results revealed the correlation of EPHA5 mutations with tumor immune microenvironment and predictive factors for immunotherapy, implying the potential of EPHA5 mutations as a prognostic marker for the prognosis of LUAD patients to immune checkpoint blockade therapy. Impact Journals 2020-12-03 /pmc/articles/PMC7834994/ /pubmed/33288738 http://dx.doi.org/10.18632/aging.202169 Text en Copyright: © 2020 Chen et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Chen, Zhiming
Chen, Ji
Ren, Dandan
Zhang, Jiao
Yang, Ying
Zhang, Henghui
Mao, Beibei
Ma, Haitao
EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma
title EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma
title_full EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma
title_fullStr EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma
title_full_unstemmed EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma
title_short EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma
title_sort epha5 mutations predict survival after immunotherapy in lung adenocarcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834994/
https://www.ncbi.nlm.nih.gov/pubmed/33288738
http://dx.doi.org/10.18632/aging.202169
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