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MODULATION OF THE TOLL-LIKE RECEPTORS SIGNALING PATHWAY AFTER INTRAVESICAL ONCOTHERAD® IMMUNOTHERAPY ASSOCIATED TO PLATELET RICH PLASMA (PRP) FOR NON-MUSCLE INVASIVE BLADDER TREATMENT
Introdução, Material, Método, Resultados, Discussão e Conclusões
There is no effective second-line therapy for non-muscle-invasive bladder cancer (NMIBC) when Bacillus Calmette-Guerin fails. In this scenario, a new perspective is represented by OncoTherad immunotherapy. OncoTherad® is a nanostructured inorganic phosphate complex associated to glycosidic protein, developed by University of Campinas/ Brazil, which exhibits antitumor properties. The use of phosphate moieties can exert biological activities, since polyphosphates are secreted by activated platelets and mast cells, interfering in innate immune response. Our research group also demonstrated that Platelet Rich Plasma (PRP) acts on immune activation and exerts antitumor effects.
This study characterized the histopathological and molecular effects of the OncoTherad® associated with PRP in the treatment of NMIBC chemically induced in mice and described the possible mechanisms of action of this association involving the Toll-like receptors (TLRs) 2 and 4 signaling pathways.
C57BL/6J mice were divided into 5 groups (n=7 animals per group): Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50mg/mL); PRP (0.1 ml); OncoTherad® (20mg/mL) and OncoTherad+PRP (1:1,10mg/mL). The intravesical doses (0.1mL) were instilled once a week for 6 consecutive weeks after induction. The urinary bladders were collected and submitted to histopathological and immunohistochemical analyzes.
Our results showed flat carcinoma in situ (pTis) in 100% of the animals from Cancer group. In this group, TLR2, IL-6, TLR4 and IRF-3 immunoreactivities were significantly lower in relation to Control, indicating suppression of the immune system in the tumor microenvironment. When treated intravesically with PRP only, animals showed 28,57% of tumor progression inhibition rate. The groups that received OncoTherad® only and OncoTherad® plus PRP showed high rates tumor progression inhibition. The combined OncoTherad and PRP treatment led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interleukins (MyD88-dependent pathway) and interferons (TRIF-dependent pathway) signaling pathways in relation to isolated treatments.
The combined OncoTherad® plus PRP treatment significantly promoted inhibition of tumor progression, possibly due to its immunomodulatory properties, including acting on the TLR pathway. This association can constitute a new therapeutic strategy for refractory NMIBC patients.
Bladder Cancer; OncoTherad; Platet Rich Plasma
Laboratório de Carcinogênese Urogenital e Imunoterapia (LCURGIM), Instituto de Biologia, Universidade Estadual de Campinas - UNICAMP - Sao Paulo - Brasil
Bianca Ribeiro de Souza Sasaki, Gabriela Cardoso de Arruda Camargo, Ianny Brum Reis, Queila Cristina Dias, Nelson Durán, Wagner José Fávaro