Systemic humoral responses of non-muscle-invasive bladder cancer during BCG treatment: less is more

Aim:Intravesical Bacille Calmette-Guérin(BCG)is the mainstay adjuvant treatment of non-muscle-invasive bladder cancer.However,one third of the patients on BCG regimen relapse within the first year of treatment.This study aimed at identifying biomarkers to predict response to BCG treatment.Methods:Gene expression was analyzed in blood cells of 58 patients treated with BCG through six consecutive weekly instillations and then at month 3,6,9,and 12.Cytokines tumor necrosis factor(TNF)-α,interleukin(IL)-10,interferon(IFN)-γ,IL-1β,IL-2,IL-4,and IL-6;chemokines CCL2,CCL3,CCL8,CXCL9,and IP-10;and mediators of cytotoxicity CTLA4,Fas-L,Perf,GNLY,NOS2A,and HMOX-1 were analyzed before the 1st and the 6th week instillation and 24 h after to assess fast(within 24 h)and prolonged changes resulting from treatment.Results:BCG instillation led to fast-increased expression of IL-1β,TNF-α,and IL-10 genes.When compared to relapsing patients,patients with no relapses within one year showed significantly lower expression of IL-1βat 1st week and less IFN-γ,HMOX-1,and GNLY at week 6.HMOX-1 and GNLY were independent predictive biomarkers,and values above the cut-off≥110 and≥13.0‰mRNA,respectively,were considered prejudicial factors.Patients with two HMOX-1 and GNLY factors had highest(66.7%)relapsing risk.Conclusion:Assessing immunomodulators’expression in blood allows the establishment of predictive cut-off values and identification of probabilities for patients’relapses after BCG treatment.