The cuproptosis-associated 11 gene signature as a predictor for outcomes and response to Bacillus Calmette-Guerin and immune checkpoint inhibitor therapies in bladder carcinoma

Abstract

Bladder cancer (BC) or carcinoma (BLCA) is predominantly derived from urothelium and includes non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Bacillus Calmette-Guerin (BCG) has long been applied for NMIBC to effectively reduce disease recurrence or progression, whereas immune checkpoint inhibitors (ICIs) were recently introduced to treat advanced BLCA with good efficacy. For BCG and ICI applications, reliable biomarkers are required to stratify potential responders for better personalized interventions, and ideally, they can replace or reduce invasive examinations such as cystoscopy in monitoring treatment efficacy. Here we developed the cuproptosis-associated 11 gene signature (CuAGS-11) model to accurately predict survival and response to BCG and ICI regimens in BLCA patients. In both discovery and validation cohorts where BLCA patients were divided into high- and low-risk groups based on a median CuAGS-11 score as the cutoff, the high-risk group was associated with significantly shortened overall survival (OS) and progression-free survival (PFS) independently. The survival predictive accuracy was comparable between CuAGS-11 and stage, and their combination-based nomograms showed high consistence between predicted and observed OS/PFS. The analysis of 3 BLCA cohorts treated with BCG unveiled lower response rates and higher frequencies of recurrence or progression coupled with shorter survival in CuAGS-11 high-risk groups. In contrast, almost none of patients underwent progression in low-risk groups. In IMvigor210 cohort of 298 BLCA patients treated with ICI Atezolizumab, complete/partial remissions were 3-fold higher accompanied by significantly longer OS in the CuAGS-11 low- than high-risk groups (P = 7.018E-06). Very similar results were obtained from the validation cohort (P = 8.65E-05). Further analyses of Tumor Immune Dysfunction and Exclusion (TIDE) scores revealed that CuAGS-11 high-risk groups displayed robustly higher T cell exclusion scores in both discovery (P = 1.96E-05) and validation (P = 0.008) cohorts. Collectively, the CuAGS-11 score model is a useful predictor for OS/PFS and BCG/ICI efficacy in BLCA patients. For BCG-treated patients, reduced invasive examinations are suggested for monitoring the CuAGS-11 low-risk patients. The present findings thus provide a framework to improve BLCA patient stratification for personalized interventions and to reduce invasive monitoring inspections.

Keywords: BCG; ICI; bladder carcinoma; cuproptosis; immunotherapy; prognosis.