Abstract: Curcumin was recently discovered to strengthen immune response through multiple mechanisms. Cytotoxic CD8⁺ T-cells play a critical role in modulating anticancer immune response, but is severely restricted by T-cell exhaustion. Bladder carcinomas express PD-L1 and can abrogate CD8⁺ T-cell response. Thus, we hypothesized that bisdemethoxycurcumin, a natural dimethoxy derivative of curcumin, may provide a favorable environment for T-cell response against bladder cancer when used in combination with α-PD-L1 antibody. Immunocompetent C56BL/6 mouse models bearing subcutaneous or lung metastasized MB79 bladder cancer were established to validate this conjecture. We found that bisdemethoxycurcumin significantly increased intratumoral CD8⁺ T-cell infiltration, elevated the level of IFN-γ in the blood, and decreased the number of intratumoral myeloid-derived suppressor cells. Furthermore, α-PD-L1 antibody protected these amplified CD8⁺ T-cells from exhaustion, and therefore facilitated the secretion of IFN-γ, granzyme B, and perforin through these CD8⁺ T-cells. As a result, this combination treatment strategy significantly prolonged survival of intraperitoneal metastasized bladder cancer bearing mice, suggesting that bisdemethoxycurcumin in combination with α-PD-L1 antibody may be promising for bladder cancer patients.
Keywords: bladder cancer, immunotherapy, bisdemethoxycurcumin, PD-L1, combination therapy, metastasis