Integrating angiogenesis signature and tumor mutation burden for improved patient stratification in immune checkpoint blockade therapy for muscle-invasive bladder cancer.

BACKGROUND:Muscle-invasive bladder cancer (MIBC) patients have benefitted greatly from immune checkpoint blockade (ICB) therapy. However, there is a pressing need to identify factors underlying the heterogeneity of clinical responses to ICB. METHODS:We conducted a study on 848 MIBC patients from 4 independent cohorts to investigate the key biological characteristics affecting ICB responses. The IMvigor210 cohort (n = 234) was used to identify the key factor, followed by exploration of the correlation between tumor angiogenesis and immune suppression in the IMvigor210, TCGA (n = 391), and UNC-108 (n = 89) cohorts. The ZSHS cohort (n = 134) was used for validation. Additionally, we integrated angiogenesis signature with tumor mutation burden (TMB) to decipher the heterogeneity of clinical outcomes to ICB in MIBC patients. RESULTS:Our analysis revealed that nonresponders to PD-L1 blockade were enriched with angiogenesis signature. Furthermore, we observed a correlation between angiogenesis signature and decreased neoantigen load, downregulated T-cell antigen recognition, and noninflamed immunophenotype. We identified a subgroup of patients resistant to ICB, characterized by high angiogenesis signature and low tumor mutation burden (TMB), and found the activation of TGF-β signaling and downregulation of T-cell cytolytic signatures in this subgroup. CONCLUSIONS:The study concluded that angiogenesis signature is closely associated with an immunosuppressive microenvironment, leading to resistance to ICB therapy in MIBC patients. The study further suggested that the combination of angiogenesis signature and TMB can serve as an integrated biomarker for better stratification of patients' clinical outcomes to ICB therapy.