Identification and validation of a dysregulated TME-related gene signature for predicting prognosis, and immunological properties in bladder cancer

Frontiers in Immunology

Immunology

Zhenqian Fan¹  Fangxin Wan²  Yinlei Wang³  Shaobo Yang³  Zhe Zhang³  Jingwen Han³  Hailong Hu³  Wang Chai³  Donghuai Wang³  Chong Shen³  Xuejing Liu⁴ 

[1] Department of Endocrinology, The Second Hospital of Tianjin Medical University, Tianjin, China;Department of Gastrointestinal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China;Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China;Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Tianjin, China;Obstetrics and Gynecology, Haidian Maternal & Child Health Hospital, Beijing, China;

关键词: bladder cancer;    tumor microenvironment (TME);    prognosis model;    immunotherapy;    drug sensitivity;   

DOI  :  10.3389/fimmu.2023.1213947

 received in 2023-04-28, accepted in 2023-10-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundDuring tumor growth, tumor cells interact with their tumor microenvironment (TME) resulting in the development of heterogeneous tumors that promote tumor occurrence and progression. Recently, there has been extensive attention on TME as a possible therapeutic target for cancers. However, an accurate TME-related prediction model is urgently needed to aid in the assessment of patients’ prognoses and therapeutic value, and to assist in clinical decision-making. As such, this study aimed to develop and validate a new prognostic model based on TME-associated genes for BC patients.MethodsTranscriptome data and clinical information for BC patients were extracted from The Cancer Genome Atlas (TCGA) database. Gene Expression Omnibus (GEO) and IMvigor210 databases, along with the MSigDB, were utilized to identify genes associated with TMEs (TMRGs). A consensus clustering approach was used to identify molecular clusters associated with TMEs. LASSO Cox regression analysis was conducted to establish a prognostic TMRG-related signature, with verifications being successfully conducted internally and externally. Gene ontology (GO), KEGG, and single-sample gene set enrichment analyses (ssGSEA) were performed to investigate the underlying mechanisms. The potential response to ICB therapy was estimated using the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and Immunophenoscore (IPS). Additionally, it was found that the expression level of certain genes in the model was significantly correlated with objective responses to anti-PD-1 or anti-PD-L1 treatment in the IMvigor210, GSE111636, GSE176307, or Truce01 (registration number NCT04730219) cohorts. Finally, real-time PCR validation was performed on 10 paired tissue samples, and in vitro cytological experiments were also conducted on BC cell lines.ResultsIn BC patients, 133 genes differentially expressed that were associated with prognosis in TME. Consensus clustering analysis revealed three distinct clinicopathological characteristics and survival outcomes. A novel prognostic model based on nine TMRGs (including C3orf62, DPYSL2, GZMA, SERPINB3, RHCG, PTPRR, STMN3, TMPRSS4, COMP) was identified, and a TMEscore for OS prediction was constructed, with its reliable predictive performance in BC patients being validated. MultiCox analysis showed that the risk score was an independent prognostic factor. A nomogram was developed to facilitate the clinical viability of TMEscore. Based on GO and KEGG enrichment analyses, biological processes related to ECM and collagen binding were significantly enriched among high-risk individuals. In addition, the low-risk group, characterized by a higher number of infiltrating CD8+ T cells and a lower burden of tumor mutations, demonstrated a longer survival time. Our study also found that TMEscore correlated with drug susceptibility, immune cell infiltration, and the prediction of immunotherapy efficacy. Lastly, we identified SERPINB3 as significantly promoting BC cells migration and invasion through differential expression validation and in vitro phenotypic experiments.ConclusionOur study developed a prognostic model based on nine TMRGs that accurately and stably predicted survival, guiding individual treatment for patients with BC, and providing new therapeutic strategies for the disease.

【 授权许可】

Unknown   
Copyright © 2023 Shen, Chai, Han, Zhang, Liu, Yang, Wang, Wang, Wan, Fan and Hu