Construction and experimental validation of a B cell senescence-related gene signature to evaluate prognosis and immunotherapeutic sensitivity in bladder cancer.

Abstract

Senescent B cells exhibit reduced antibody production and enhanced proinflammatory cytokine and chemokine secretion, exerting non-negligible functions in antitumor immunity. This study aims to clarify the prognosis value of B cell senescence-related genes in bladder cancer (BLCA). Twelve B cell senescence-related genes were identified based on previous studies and the single-cell RNA sequencing of a BLCA sample from Gene Expression Omnibus (GEO). The Cancer Genome Atlas BLCA cohort was used as the training dataset. Three cohorts from GEO, 35 clinical samples from the local hospital, and in vitro cell experiments were used for validation. The unsupervised clustering based on the 12 genes was associated with the prognosis and the tumor immunity. Through least absolute shrinkage and selection operator regression and random forest algorithm, G protein subunit gamma 11 (GNG11) and inhibitor of DNA binding 1 (ID1) of the 12 genes were determined as significant prognosis predictors and then included in the multivariate Cox regression model. The model was a reliable and robust prognosis biomarker across multiple large-scale cohorts (pooled HR = 1.76, 95% CI = 1.41-2.20). The tight association between the model and BLCA malignant degree was demonstrated in the local cohort (P < 0.01). The model could also predict the immunotherapeutic sensitivity, which was confirmed by the tumor immune dysfunction and exclusion algorithm (P < 0.0001) and IMvigor210 cohort (P < 0.0001). At last, in vitro cell experiments in IM-9 and GM12878 B cells indicated that GNG11 and ID1 were involved in the cellular aging process. Collectively, a B cell senescence-related gene signature was constructed to evaluate the prognosis and immunotherapeutic response in BLCA, providing novel insights into the biological mechanisms.