Dados do Trabalho

Título

ONCOTHERAD® INTRAVESICAL NANO-IMMUNOTHERAPY ASSOCIATED TO PLATELET RICH PLASMA MODULATES IFN-GAMMA PRODUCTION AND JAK-STAT SIGNALING PATHWAY IN BLADDER CANCER

Introdução

Several immune regulatory processes are mediated by Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, including those involved in antitumor immunity. Antitumor immune responses are largely driven by JAK1 and JAK2 induction of interferons (IFNs), mainly IFN-γ, and the downstream programs IFNs potentiate. The use of Toll-like Receptors (TLRs) inducers is gaining fast momentum in the field of cancer therapeutics. OncoTherad® nano-immunotherapy stimulates TLRs 2 and 4, resulting in an increased activation of the IFNs. Previous studies have shown that Platelet Rich Plasma (PRP) also acts on immune activation.

Objetivo

The study aimed to evaluate the effects of OncoTherad® intravesical treatment associated to PRP on JAK1/JAK2/STAT3 signaling in a mouse model of non-muscle invasive bladder cancer (NMIBC).

Método

C57BL/6J mice were distributed into groups (n=7/group): Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50mg/ml); PRP (0.1 ml); OncoTherad® (20mg/ml) and OncoTherad®+PRP (1:1,10mg/ml). Intravesical doses (0.1ml) were instilled once a week for 6 consecutive weeks after NMIBC induction. The immunohistochemical analyzes were evaluated in two ways: total immunoreactivity (percentage of positive cells) and intensity of immunoreaction.

Resultado

OncoTherad® immunotherapy alone or combined with PRP showed the highest percentages of positive cells for IFN-γ (91.3% and 90.1% respectively) in comparison with the Cancer group (p<0.05), showing strong immunoreaction in the urothelium. In contrast, Cancer group showed the lowest IFN-γ total immunoreactivity (68.8%) and a weaker immunoreaction. The highest percentages of positive cells for JAK1 (97.4%) and STAT3 (93.8%) were found in the PRP group as compared to the other experimental groups (p<0.05), showing a strong immunoreaction. OncoTherad® treatment alone was more effective in reducing (p<0.05) STAT3 total immunoreactivity, showing weak immunoreaction compared to other treatments. OncoTherad® plus PRP increased the percentage of positive cells and the intensity of immunoreaction for JAK2 (p<0.05) as compared to PRP and OncoTherad® alone treatments.

Conclusão

JAK-STAT signaling appears to be involved in urothelial carcinogenesis. Combined treatment with OncoTherad® plus PRP stimulated IFN-γ production, resulting in activation of JAK-STAT pathway, which, in turn, stimulates further the production of IFN-γ. This feed-forward loop might have implications in T cell-mediated antitumor activity and restraining tumor growth.

Palavras-chave

Bladder cancer, Immunotherapy, JAK-STAT Signaling