Blocking IL-10 enhances bacillus Calmette-Guérin induced T helper Type 1 immune responses and anti-bladder cancer immunity

Abstract

Proper induction of Th1 immunity is required for effective immunotherapy of bladder cancer with the bacillus Calmette-Guérin (BCG). Interleukin-10 (IL-10) downregulates the Th1 immune response and is associated with BCG therapy failure. We evaluated BCG plus IL-10 blocking antibodies and found that this combination therapy induces enhanced Th1 immune responses and anti-bladder cancer immunity in preclinical animal models.

Figure 1. Suggested cascade of immune responses in bladder mucosa induced by intravesical bacillus Calmette-Guérin (BCG) instillation. Attachment of BCG to urothelial cells including carcinoma cells triggers the release of cytokines and chemokines, resulting in the recruitment of various types of immune cells into the bladder wall. Activation of phagocytes and the cytokine environment lead to the differentiation of naïve CD4⁺ T cells into Th1 and/or Th2 cells, which further direct immune responses toward cellular or humoral immunity, respectively. The therapeutic effect of BCG depends on a proper induction of Th1 immune responses. Interleukin-10 (IL-10) inhibits Th1 immune responses whereas interferon γ (IFNγ) inhibits Th2 immune responses. Thus, blocking IL-10 or inducing IFNγ can lead to a Th1-dominated immunity that is essential for the BCG-mediated bladder cancer resolution.