Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma

Objective: Resistance to immune checkpoint inhibitors (ICIs) has been a massive obstacle to ICI treatment in metastatic urothelial carcinoma (MUC). Recently, increasing evidence indicates the clinical importance of the association between hypoxia and immune status in tumor patients. Therefore, it is...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Shuo Hong, Yueming Zhang, Manming Cao, Anqi Lin, Qi Yang, Jian Zhang, Peng Luo, Linlang Guo
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	metastatic urothelial carcinoma prognosis model immune checkpoint inhibitors hypoxia immune microenvironment Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/03debf4e76a9449d86dfbfc4f9da5528
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:03debf4e76a9449d86dfbfc4f9da5528
record_format	dspace
spelling	oai:doaj.org-article:03debf4e76a9449d86dfbfc4f9da55282021-12-01T02:51:11ZHypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma2296-634X10.3389/fcell.2021.762478https://doaj.org/article/03debf4e76a9449d86dfbfc4f9da55282021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.762478/fullhttps://doaj.org/toc/2296-634XObjective: Resistance to immune checkpoint inhibitors (ICIs) has been a massive obstacle to ICI treatment in metastatic urothelial carcinoma (MUC). Recently, increasing evidence indicates the clinical importance of the association between hypoxia and immune status in tumor patients. Therefore, it is necessary to investigate the relationship between hypoxia and prognosis in metastatic urothelial carcinoma.Methods: Transcriptomic and clinical data from 348 MUC patients who underwent ICI treatment from a large phase 2 trial (IMvigor210) were investigated in this study. The cohort was randomly divided into two datasets, a training set (n = 213) and a testing set (n = 135). Data of hypoxia-related genes were downloaded from the molecular signatures database (MSigDB), and screened by univariate and multivariate Cox regression analysis to construct a prognosis-predictive model. The robustness of the model was evaluated in two melanoma cohorts. Furthermore, an external validation cohort, the bladder cancer cohort, from the Cancer Genome Atlas (TCGA) database, was t used to explore the mechanism of gene mutation, immune cell infiltration, signaling pathway enrichment, and drug sensitivity.Results: We categorized patients as the high- or low- risk group using a four-gene hypoxia risk model which we constructed. It was found that patients with high-risk scores had significantly worse overall survival (OS) compared with those with low-risk scores. The prognostic model covers 0.71 of the area under the ROC curve in the training set and 0.59 in the testing set, which is better than the survival prediction of MUC patients using the clinical characteristics. Mutation analysis results showed that deletion mutations in RB1, TP53, TSC1 and KDM6A were correlated with hypoxic status. Immune cell infiltration analysis illustrated that the infiltration T cells, B cells, Treg cells, and macrophages was correlated with hypoxia. Functional enrichment analysis revealed that a hypoxic microenvironment activated inflammatory pathways, glucose metabolism pathways, and immune-related pathways.Conclusion: In this investigation, a four-gene hypoxia risk model was developed to evaluate the degree of hypoxia and prognosis of ICI treatment, which showed a promising clinical prediction value in MUC. Furthermore, the hypoxia risk model revealed a close relationship between hypoxia and the tumor immune microenvironment.Shuo HongYueming ZhangManming CaoAnqi LinQi YangJian ZhangPeng LuoLinlang GuoFrontiers Media S.A.articlemetastatic urothelial carcinomaprognosis modelimmune checkpoint inhibitorshypoxiaimmune microenvironmentBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	metastatic urothelial carcinoma prognosis model immune checkpoint inhibitors hypoxia immune microenvironment Biology (General) QH301-705.5
spellingShingle	metastatic urothelial carcinoma prognosis model immune checkpoint inhibitors hypoxia immune microenvironment Biology (General) QH301-705.5 Shuo Hong Yueming Zhang Manming Cao Anqi Lin Qi Yang Jian Zhang Peng Luo Linlang Guo Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma
description	Objective: Resistance to immune checkpoint inhibitors (ICIs) has been a massive obstacle to ICI treatment in metastatic urothelial carcinoma (MUC). Recently, increasing evidence indicates the clinical importance of the association between hypoxia and immune status in tumor patients. Therefore, it is necessary to investigate the relationship between hypoxia and prognosis in metastatic urothelial carcinoma.Methods: Transcriptomic and clinical data from 348 MUC patients who underwent ICI treatment from a large phase 2 trial (IMvigor210) were investigated in this study. The cohort was randomly divided into two datasets, a training set (n = 213) and a testing set (n = 135). Data of hypoxia-related genes were downloaded from the molecular signatures database (MSigDB), and screened by univariate and multivariate Cox regression analysis to construct a prognosis-predictive model. The robustness of the model was evaluated in two melanoma cohorts. Furthermore, an external validation cohort, the bladder cancer cohort, from the Cancer Genome Atlas (TCGA) database, was t used to explore the mechanism of gene mutation, immune cell infiltration, signaling pathway enrichment, and drug sensitivity.Results: We categorized patients as the high- or low- risk group using a four-gene hypoxia risk model which we constructed. It was found that patients with high-risk scores had significantly worse overall survival (OS) compared with those with low-risk scores. The prognostic model covers 0.71 of the area under the ROC curve in the training set and 0.59 in the testing set, which is better than the survival prediction of MUC patients using the clinical characteristics. Mutation analysis results showed that deletion mutations in RB1, TP53, TSC1 and KDM6A were correlated with hypoxic status. Immune cell infiltration analysis illustrated that the infiltration T cells, B cells, Treg cells, and macrophages was correlated with hypoxia. Functional enrichment analysis revealed that a hypoxic microenvironment activated inflammatory pathways, glucose metabolism pathways, and immune-related pathways.Conclusion: In this investigation, a four-gene hypoxia risk model was developed to evaluate the degree of hypoxia and prognosis of ICI treatment, which showed a promising clinical prediction value in MUC. Furthermore, the hypoxia risk model revealed a close relationship between hypoxia and the tumor immune microenvironment.
format	article
author	Shuo Hong Yueming Zhang Manming Cao Anqi Lin Qi Yang Jian Zhang Peng Luo Linlang Guo
author_facet	Shuo Hong Yueming Zhang Manming Cao Anqi Lin Qi Yang Jian Zhang Peng Luo Linlang Guo
author_sort	Shuo Hong
title	Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma
title_short	Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma
title_full	Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma
title_fullStr	Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma
title_full_unstemmed	Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma
title_sort	hypoxic characteristic genes predict response to immunotherapy for urothelial carcinoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/03debf4e76a9449d86dfbfc4f9da5528
work_keys_str_mv	AT shuohong hypoxiccharacteristicgenespredictresponsetoimmunotherapyforurothelialcarcinoma AT yuemingzhang hypoxiccharacteristicgenespredictresponsetoimmunotherapyforurothelialcarcinoma AT manmingcao hypoxiccharacteristicgenespredictresponsetoimmunotherapyforurothelialcarcinoma AT anqilin hypoxiccharacteristicgenespredictresponsetoimmunotherapyforurothelialcarcinoma AT qiyang hypoxiccharacteristicgenespredictresponsetoimmunotherapyforurothelialcarcinoma AT jianzhang hypoxiccharacteristicgenespredictresponsetoimmunotherapyforurothelialcarcinoma AT pengluo hypoxiccharacteristicgenespredictresponsetoimmunotherapyforurothelialcarcinoma AT linlangguo hypoxiccharacteristicgenespredictresponsetoimmunotherapyforurothelialcarcinoma
_version_	1718405882852671488

Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma

Ejemplares similares