Construction of T cell exhaustion model for predicting survival and immunotherapy effect of bladder cancer based on WGCNA

Abstract

IntroductionThe prognosis of bladder cancer (BLCA) and response to immune checkpoint inhibitors (ICIs) are determined by multiple factors. Existed biomarkers for predicting the effect of immunotherapy cannot accurately predict the response of BLCA patients to ICIs.MethodsTo further accurately stratify patients’ response to ICIs and identify potential novel predictive biomarkers, we used the known T cell exhaustion (TEX)-related specific pathways, including tumor necrosis factor (TNF), interleukin (IL)-2, interferon (IFN)-g, and T- cell cytotoxicpathways, combined with weighted correlation network analysis (WGCNA) to analyze the characteristics of TEX in BLCA in detail, constructed a TEX model.ResultsThis model including 28 genes can robustly predict the survival of BLCA and immunotherapeutic efficacy. This model could divide BLCA into two groups, TEXhigh and TEXlow, with significantly different prognoses, clinical features, and reactivity to ICIs. The critical characteristic genes, such as potential biomarkers Charged Multivesicular Body Protein 4C (CHMP4C), SH2 Domain Containing 2A (SH2D2A), Prickle Planar Cell Polarity Protein 3 (PRICKLE3) and Zinc Finger Protein 165 (ZNF165) were verified in BLCA clinical samples by real-time quantitative chain reaction (qPCR) and immunohistochemistry (IHC).DiscussionOur findings show that the TEX model can serve as biological markers for predicting the response to ICIs, and the involving molecules in the TEX model might provide new potential targets for immunotherapy in BLCA.

Comprehensive analysis of T cell exhaustion related signature for predicting prognosis and immunotherapy response in HNSCC

“…We utilized single-sample gene set enrichment analysis (ssGSEA), implemented through the ‘GSVA’ R package [ 20 ], to estimate the enrichment score of TEX-related pathways for each patients. Similar to previous studies, TEX-related pathway was represented by interleukin (IL)-2, tumor necrosis factor (TNF), interferon-γ (IFN-γ) and cytotoxic potential (CTL) [ 21 , 22 ]. The gene sets corresponding to TEX-related pathways were obtained from Molecular Signatures Database ( https://www.gsea-msigdb.org/gsea/msigdb , accessed on 24 February 2023).…”

The combination of transcriptome and Mendelian randomization reveals clinical and immuno-functional biomarkers of alternative splicing regulation associated with planar cell polarity signaling pathways in pan-cancer

“…PRICKLE3, a protein-coding gene in the PCP signaling pathway, is primarily involved in regulating cell polarity and tissue development 39 . Previous research has suggested that PRICKLE3 is signi cantly upregulated in bladder cancer tissues and may be linked to tumor invasion and prognosis 40 . Our ndings demonstrated that high PRICKLE3 expression was associated with poorer OS in tumor patients, particularly in males and those with higher age, advanced stage, higher T, and higher N stage.…”