Cargando…

EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma

BACKGROUND: Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHA(mut)) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated...

Descripción completa

Detalles Bibliográficos
Autores principales: Bai, Hua, Duan, Jianchun, Li, Chengcheng, Xie, Wenzhuan, Fang, Wenfeng, Xu, Yu, Wang, Guoqiang, Wan, Rui, Sun, Jing, Xu, Jiachen, Wang, Xin, Fei, Kailun, Zhao, Zhengyi, Cai, Shangli, Zhang, Li, Wang, Jie, Wang, Zhijie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733211/
https://www.ncbi.nlm.nih.gov/pubmed/33303576
http://dx.doi.org/10.1136/jitc-2020-001315
_version_ 1783622229773254656
author Bai, Hua
Duan, Jianchun
Li, Chengcheng
Xie, Wenzhuan
Fang, Wenfeng
Xu, Yu
Wang, Guoqiang
Wan, Rui
Sun, Jing
Xu, Jiachen
Wang, Xin
Fei, Kailun
Zhao, Zhengyi
Cai, Shangli
Zhang, Li
Wang, Jie
Wang, Zhijie
author_facet Bai, Hua
Duan, Jianchun
Li, Chengcheng
Xie, Wenzhuan
Fang, Wenfeng
Xu, Yu
Wang, Guoqiang
Wan, Rui
Sun, Jing
Xu, Jiachen
Wang, Xin
Fei, Kailun
Zhao, Zhengyi
Cai, Shangli
Zhang, Li
Wang, Jie
Wang, Zhijie
author_sort Bai, Hua
collection PubMed
description BACKGROUND: Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHA(mut)) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC). METHODS: Multiple cohorts were used to assess the immunotherapeutic predictive performance of EPHA(mut), including one discovery cohort (n=79) and two public validation cohort (cohort 1: NSCLC, n=165; cohort 2: pan-cancer, n=1662). The Cancer Genome Atlas cohort was used for prognostic analysis and mechanism exploration. RESULTS: In the discovery cohort, patients with EPHA(mut) had superior disease control rate (72.2% vs 36.1%, p=0.01) and progression-free survival (PFS) (HR 0.38; 95% CI 0.21 to 0.68; p<0.001) compared with those with wide-type EPHA (EPHA(wt)) in NSCLC. The association between EPHA(mut) and immunotherapy outcomes in NSCLC was consistently observed in the validation cohorts by multivariable models (cohort 1, PFS HR 0.59; 95% CI 0.37 to 0.96; p=0.03; cohort 2, overall survival (OS) HR 0.63; 95% CI 0.41 to 0.98; p=0.04). Further pooled estimates of the discovery and validation cohorts showed that patients with EPHA(mut) exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC). Consistently, mechanism analysis revealed that patients with EPHA(mut) was associated with increased T cell signatures and downregulated transforming growth factor-β signaling compared with patients with EPHA(wt) in LUAD while not LUSC. CONCLUSIONS: Our results demonstrated that EPHA(mut) is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted. TRIAL REGISTRATION NUMBER: NCC2016JZ-03, NCC2018-092.
format Online
Article
Text
id pubmed-7733211
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-77332112020-12-21 EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma Bai, Hua Duan, Jianchun Li, Chengcheng Xie, Wenzhuan Fang, Wenfeng Xu, Yu Wang, Guoqiang Wan, Rui Sun, Jing Xu, Jiachen Wang, Xin Fei, Kailun Zhao, Zhengyi Cai, Shangli Zhang, Li Wang, Jie Wang, Zhijie J Immunother Cancer Immunotherapy Biomarkers BACKGROUND: Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHA(mut)) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC). METHODS: Multiple cohorts were used to assess the immunotherapeutic predictive performance of EPHA(mut), including one discovery cohort (n=79) and two public validation cohort (cohort 1: NSCLC, n=165; cohort 2: pan-cancer, n=1662). The Cancer Genome Atlas cohort was used for prognostic analysis and mechanism exploration. RESULTS: In the discovery cohort, patients with EPHA(mut) had superior disease control rate (72.2% vs 36.1%, p=0.01) and progression-free survival (PFS) (HR 0.38; 95% CI 0.21 to 0.68; p<0.001) compared with those with wide-type EPHA (EPHA(wt)) in NSCLC. The association between EPHA(mut) and immunotherapy outcomes in NSCLC was consistently observed in the validation cohorts by multivariable models (cohort 1, PFS HR 0.59; 95% CI 0.37 to 0.96; p=0.03; cohort 2, overall survival (OS) HR 0.63; 95% CI 0.41 to 0.98; p=0.04). Further pooled estimates of the discovery and validation cohorts showed that patients with EPHA(mut) exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC). Consistently, mechanism analysis revealed that patients with EPHA(mut) was associated with increased T cell signatures and downregulated transforming growth factor-β signaling compared with patients with EPHA(wt) in LUAD while not LUSC. CONCLUSIONS: Our results demonstrated that EPHA(mut) is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted. TRIAL REGISTRATION NUMBER: NCC2016JZ-03, NCC2018-092. BMJ Publishing Group 2020-12-10 /pmc/articles/PMC7733211/ /pubmed/33303576 http://dx.doi.org/10.1136/jitc-2020-001315 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Immunotherapy Biomarkers
Bai, Hua
Duan, Jianchun
Li, Chengcheng
Xie, Wenzhuan
Fang, Wenfeng
Xu, Yu
Wang, Guoqiang
Wan, Rui
Sun, Jing
Xu, Jiachen
Wang, Xin
Fei, Kailun
Zhao, Zhengyi
Cai, Shangli
Zhang, Li
Wang, Jie
Wang, Zhijie
EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma
title EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma
title_full EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma
title_fullStr EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma
title_full_unstemmed EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma
title_short EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma
title_sort epha mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma
topic Immunotherapy Biomarkers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733211/
https://www.ncbi.nlm.nih.gov/pubmed/33303576
http://dx.doi.org/10.1136/jitc-2020-001315
work_keys_str_mv AT baihua ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT duanjianchun ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT lichengcheng ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT xiewenzhuan ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT fangwenfeng ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT xuyu ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT wangguoqiang ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT wanrui ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT sunjing ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT xujiachen ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT wangxin ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT feikailun ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT zhaozhengyi ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT caishangli ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT zhangli ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT wangjie ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma
AT wangzhijie ephamutationasapredictorofimmunotherapeuticefficacyinlungadenocarcinoma