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Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma

Accumulating evidence has suggested the impact of senescence on tumor progression, but no report has yet described how senescence shapes the tumor microenvironment of clear cell renal cell carcinoma (ccRCC). The objective of this study was to delineate the senescence features of ccRCC and its role i...

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Autores principales: Zhou, Peng, Liu, Zheng, Hu, Henglong, Lu, Yuchao, Xiao, Jun, Wang, Yanan, Xun, Yang, Xia, Qidong, Liu, Chenqian, Hu, Jia, Wang, Shaogang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201070/
https://www.ncbi.nlm.nih.gov/pubmed/35720278
http://dx.doi.org/10.3389/fimmu.2022.901671
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author Zhou, Peng
Liu, Zheng
Hu, Henglong
Lu, Yuchao
Xiao, Jun
Wang, Yanan
Xun, Yang
Xia, Qidong
Liu, Chenqian
Hu, Jia
Wang, Shaogang
author_facet Zhou, Peng
Liu, Zheng
Hu, Henglong
Lu, Yuchao
Xiao, Jun
Wang, Yanan
Xun, Yang
Xia, Qidong
Liu, Chenqian
Hu, Jia
Wang, Shaogang
author_sort Zhou, Peng
collection PubMed
description Accumulating evidence has suggested the impact of senescence on tumor progression, but no report has yet described how senescence shapes the tumor microenvironment of clear cell renal cell carcinoma (ccRCC). The objective of this study was to delineate the senescence features of ccRCC and its role in shaping the tumor microenvironment through a comprehensive analysis of multiple datasets, including 2,072 ccRCC samples. Unsupervised consensus clustering identified three senescence subtypes, and we found that the senescence-activated subtype survived the worst, even in the condition of targeted therapy and immunotherapy. The activated senescence program was correlated to increased genomic instability, unbalanced PBMR1/BAP1 mutations, elevated immune cell infiltration, and enhanced immune inhibitory factors (cancer-associated fibroblasts, immune suppression, immune exclusion, and immune exhaustion signaling). A senescence score based on nine senescence-related genes (i.e., P3H1, PROX1, HJURP, HK3, CDKN1A, AR, VENTX, MAGOHB, and MAP2K6) was identified by adaptive lasso regression and showed robust prognostic predictive power in development and external validation cohorts. Notably, we found that the senescence score was correlated to immune suppression, and the low-score subgroup was predicted to respond to anti–PD-1 therapy, whereas the high-score subgroup was predicted to respond to Sunitinib/Everolimus treatment. Collectively, senescence acted as an active cancer hallmark of ccRCC, shaped the immune microenvironment, and profoundly affected tumor prognosis and drug treatment response.
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spelling pubmed-92010702022-06-17 Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma Zhou, Peng Liu, Zheng Hu, Henglong Lu, Yuchao Xiao, Jun Wang, Yanan Xun, Yang Xia, Qidong Liu, Chenqian Hu, Jia Wang, Shaogang Front Immunol Immunology Accumulating evidence has suggested the impact of senescence on tumor progression, but no report has yet described how senescence shapes the tumor microenvironment of clear cell renal cell carcinoma (ccRCC). The objective of this study was to delineate the senescence features of ccRCC and its role in shaping the tumor microenvironment through a comprehensive analysis of multiple datasets, including 2,072 ccRCC samples. Unsupervised consensus clustering identified three senescence subtypes, and we found that the senescence-activated subtype survived the worst, even in the condition of targeted therapy and immunotherapy. The activated senescence program was correlated to increased genomic instability, unbalanced PBMR1/BAP1 mutations, elevated immune cell infiltration, and enhanced immune inhibitory factors (cancer-associated fibroblasts, immune suppression, immune exclusion, and immune exhaustion signaling). A senescence score based on nine senescence-related genes (i.e., P3H1, PROX1, HJURP, HK3, CDKN1A, AR, VENTX, MAGOHB, and MAP2K6) was identified by adaptive lasso regression and showed robust prognostic predictive power in development and external validation cohorts. Notably, we found that the senescence score was correlated to immune suppression, and the low-score subgroup was predicted to respond to anti–PD-1 therapy, whereas the high-score subgroup was predicted to respond to Sunitinib/Everolimus treatment. Collectively, senescence acted as an active cancer hallmark of ccRCC, shaped the immune microenvironment, and profoundly affected tumor prognosis and drug treatment response. Frontiers Media S.A. 2022-06-02 /pmc/articles/PMC9201070/ /pubmed/35720278 http://dx.doi.org/10.3389/fimmu.2022.901671 Text en Copyright © 2022 Zhou, Liu, Hu, Lu, Xiao, Wang, Xun, Xia, Liu, Hu and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhou, Peng
Liu, Zheng
Hu, Henglong
Lu, Yuchao
Xiao, Jun
Wang, Yanan
Xun, Yang
Xia, Qidong
Liu, Chenqian
Hu, Jia
Wang, Shaogang
Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma
title Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma
title_full Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma
title_fullStr Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma
title_full_unstemmed Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma
title_short Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma
title_sort comprehensive analysis of senescence characteristics defines a novel prognostic signature to guide personalized treatment for clear cell renal cell carcinoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201070/
https://www.ncbi.nlm.nih.gov/pubmed/35720278
http://dx.doi.org/10.3389/fimmu.2022.901671
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