PD12-11: Castration Impact on Pattern Recognition Receptors (PRRs) Boosts Toll-Like Receptor-4 Expression in an Immunocompetent Bladder Cancer Male Model

Leonardo Reis*, Campinas, Brazil

Introduction: Among diverse Pattern Recognition Receptors (PRRs), the Toll-Like Receptor-4 (TLR-4) is the key urothelial trigger for innate immune response and plays a central role as Bacillus Calmette Guerin (BCG) main target. Also, its gene polymorphism and expression are associated to bladder cancer (BCa) prognosis. Androgen activation promotes immunotolerance, playing an immunoregulatory role, though by unknown mechanisms.

Methods: We described an efficient male immunocompetent BCa animal model. Intact (sham) versus castrated male Fisher-344 rats were evaluated in 2 scenarios: A) Carcinogenesis: After randomization to SHAM (n=5) and Castration (n=5), carcinogenesis was induced by four intravesical doses of 1.5 mg/kg n-methyl-n-nitrosourea (MNU) every 15 days. B) Treatment: After ultrasonographic confirmed MNU induced papillary BCa on week 8, rats were randomized to SHAM (n=5) and Castration (N=5) and offered 6 weekly intravesical treatment of 106 CFU of BCG in 0.2 ml saline. After 15 weeks of protocol, animals were euthanized and the urinary bladders submitted to histopathology, immunohistochemistry (IHC), and Western blotting (WB). Urothelial cell proliferation was measured by Ki-67 IHC and TLR-4 expression quantified by IHC and WB.

Results: Castration induced higher TLR-4 urothelial expression (p=.007) and anticarcinogenic effect with less urothelial tumors (60 vs. 80%) and lower urothelial cell proliferation compared to intact animals (p=.008). In the intravesical BCG treatment setting, castration has potentialized the BCG activation of TLR-4 (p=.007) with no residual in situ carcinoma compared to intact animals, suggesting the potential to amplify the immune initiation phase activated by BCG.

Conclusions: To our knowledge, this is the first description of TLR-4 urothelial expression hormonal modulation. The described male immunocompetent animal model will help to improve the knowledge of urothelial cancer gender diversities and PRRs modulations with treatment implications.

Source of Funding: none