Comprehensive Analysis Based on the Cancer-Immunity Cycle Identifies a Novel Immunosuppressive Subtype of Bladder Cancer.

[BACKGROUND] Immune checkpoint blockade (ICB) has reshaped the approach to treating a broad spectrum of cancers, including bladder cancer (BLCA). However, a substantial fraction of BLCA patients still exhibit resistance despite high programmed death-ligand 1(PD-L1) expression in the tumor. Consequently, it is imperative to characterize the tumor immunosuppressive microenvironment (TME) and ascertain key biomarkers associated with immune evasion in order to stratify patients according to their propensity for immunotherapy resistance.

[METHODS] A retrospective analysis of RNA sequencing data sourced from 403 BLCA samples was conducted during the course of our experimental research. Our research team employed weighted gene coexpression network profiling (WGCNA) and machine learning models to uncover tumor-immune cycle-associated genes that are tightly linked to BLCA. Unsupervised clustering was implemented to explore the tumor microenvironment-associated gene expression profiles. Subsequently, in turn, we drew correlations between these expression signatures and a group of T cell exhaustion indicators, receptors, and immunotherapy responsiveness to further categorize them. Finally, a set of experiments were executed to verify the putative role of the core gene BIRC5 in BLCA at the experimental level.

[RESULTS] Through comprehensive analysis, BIRC5, HSPA12A, and CXCL12 were identified as hub genes. Additionally, based on the molecular expression profiles of these three hub genes, BLCA patients were stratified into distinct subgroups. Simultaneously, this classification was correlated with the immune microenvironment landscape and established the exhausted immune class (EIC)-a novel subtype with high PD-L1 expression, exhausted T cell markers, and immunosuppressive cytokines-in BLCA patients. Finally, we confirmed that BIRC5 exhibited high expression levels in BLCA and was involved in modulating the malignant proliferation, migratory activity, and invasive behavior of BLCA cells in vitro.

[CONCLUSION] The investigative group validated the oncogenic activity of BIRC5, a gene correlated with the tumor-immune cycle. Additionally, our research team has identified a novel molecular subtype of BLCA that exhibits high expression of PD-L1 but may potentially exhibit resistance to ICB therapy. These findings offer valuable insights into comprehensively characterizing the immunosuppressive tumor microenvironment in BLCA and present opportunities for deepened scrutiny of immunotherapy resistance mechanisms and optimization of targeted immunotherapeutic regimens.