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

Abstract

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 CDIhigh (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 CDIhigh group. Besides, the CDIhigh 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 CDIhigh risk who might suffer progression and be more suitable to benefit from immune checkpoint inhibitors or other immunotherapies.

Exploration of the prognostic effect of costimulatory genes in bladder cancer

“…This interaction has been implicated in immune system evasion by bladder cancer cells, contributing to disease progression and poor patient outcomes. The expression level of CD276 [39][40][41]…”

“…This interaction has been implicated in immune system evasion by bladder cancer cells, contributing to disease progression and poor patient outcomes. The expression level of CD276 39–41 in bladder cancer has been shown to be associated with tumor invasion, metastasis, and poor prognosis. Patients with bladder cancer with high CD276 expression have a poorer prognosis, according to an independent predictor.…”

Can uric acid affect the immune microenvironment in bladder cancer? A single‐center multi‐omics study

“…All immune cells in the high‐risk group were lesser than those in the low‐risk group, particularly CD8 + T and NK cells. Exhausted infiltrating immune cells were associated with poor BCa prognosis and BCG failure, 61,62 which might partially account for the significantly decreased survival of patients with high UA levels. In addition, reinvigorated CD8 + T cells predict the efficacy of PD‐1 and TIGIT immunotherapy 63 .…”

Identification of adenylate cyclase 2 methylation in bladder cancer with implications for prognosis and immunosuppressive microenvironment

“…Chemotherapy is still the primary treatment option in the late stage which includes gemcitabine, cisplatin, carboplatin, paclitaxel, and others (3). However, immunotherapy, targeted therapy, and antibody-coupled drugs are gradually used for the treatment (4,5), which helps improve the survival rate of patients (6). The most recent clinical studies comprehensively cover all stages of BCa, including the use of new generations of antibody-coupled drugs, targeted drugs, oncolytic viruses, immunomab, dual antibodies, and others (7,8).…”

“…The most recent clinical studies comprehensively cover all stages of BCa, including the use of new generations of antibody-coupled drugs, targeted drugs, oncolytic viruses, immunomab, dual antibodies, and others (7,8). The diagnosis and treatment model of early diagnosis, refined surgery, comprehensive multidisciplinary process, and internationalization of clinical translational research were proposed, which significantly improved the diagnosis and treatment of BCa in China (4).…”