Immunogenomic Characteristics of Cell-Death-Associated Genes with Prognostic Implications in Bladder Cancer

Bladder cancer is one of the most common genitourinary malignant cancers worldwide. Cell death processes, including apoptosis, ferroptosis, and necrosis, provide novel clinical and immunological insights promoting the management of precision medicine. Therefore, this study aimed to evaluate the transcriptomic profile of signatures in cell death pathways with significant prognostic implications in patients with bladder cancer from multiple independent cohorts (n = 1999). First, genes involved in apoptosis (n = 19), ferroptosis (n = 31), and necrosis (n = 6) were analyzed to evaluate the prognostic implications in bladder cancer. Significant genes were included to establish the cell-death index (CDI) of 36 genes that distinguished patients according to high and low risks. Survival analysis using the Kaplan-Meier curves clustered patients based on overall survival (18.8 vs. 96.7 months; hazard model [HR] = 3.12, P<00001). Cox proportional hazard model was significantly associated with a higher risk of mortality using 10 external independent cohorts in patients with CDI^high (HR = 1.31, 95% CI: 1.04-1.62). To explore immune parameters associated with CDI, microenvironment cell-population-counter algorithms indicated increased intratumoral heterogeneity and macrophage/monocyte infiltration and CD8⁺ T cells in patients with CDI^high group. Besides, the CDI^high group showed an increased expression of the following immune checkpoints: CD276, PD-L1, CTLA-4, and T-cell exhaustion signatures. Cytokine expression analysis revealed the highest association of IL-9R, IL-17A, IL-17F, GDF7, and IFNW1 with the high-risk group. In addition, 42 patients with BCa receiving immunotherapies were enrolled from a real-world cohort, and expression patterns of three CDI hub genes (DRD5, SCL2A14, and IGF1) were detected using immunohistochemical staining. Patients with triple-negative staining of tumor tissues had significantly higher tumor-associated macrophage abundance, PD-L1 expression, predicted immunocompromised microenvironment, and prominently progressive progression (HR = 4.316, P = 0.0028). In conclusion, this study highlights the immunoevasive tumor microenvironment characterized by the higher tumor-associated macrophage infiltration with the presence of immune checkpoint and T-cell exhaustion genes in patients with BCa at CDI^high risk who might suffer progression and be more suitable to benefit from immune checkpoint inhibitors or other immunotherapies.