Effect of the P-MAPA immunomodulator associated with interleukin-12 in the ovarian carcinoma of Fischer 344 rats: approach of the inflammatory process and immune system

Author(s)

Henrique Spaulonci Silveira

• Document type: Master's Dissertation
• Press: Botucatu. 2020-04-03.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências. Botucatu
• Defense date: 2020-02-21
• Advisor: Luiz Gustavo de Almeida Chuffa

Abstract

Ovarian cancer (OC) is the second most lethal among gynecological malignancies and many women acquire chemoresistance associated with the inflammatory process. Interleukin-12 (IL-12) is responsible for the inflammatory T helper 1 (Th1) response and the protein aggregate of ammonium and magnesium phospholinoleate and palmitoleate anhydride (P-MAPA) acts as an immunostimulatory agent in aggressive cancers. This study investigated the functional treatments with P-MAPA and IL-12 on the inflammatory process and on the OC-related immune cells in an in vivo model. OCs were chemically induced with 7,12-dimethylbenz(a)anthracene (DMBA) into the ovarian bursa, and after developing tumors, the animals were given P-MAPA, IL-12, or P-MAPA combined with IL-12. The combinatory therapy improved the general features of OC, contributing to a reduction in the inflammatory cells, adipocyte accumulation in addition to revealing a soft and mobile tissue with no adherences and peritoneal implants. P-MAPA treatment increased the levels of TLR2, TLR4 and TRIF in OCs while decreased the number of T regulatory (Treg) cells (CD4+CD25+/FoxP-3+ and CD8+FoxP-3+). Additionally, the association of P-MAPA with IL-12 significantly stimulated the CD4+ and CD8+ T cell effector in draining lymphnodes. Regarding to the inflammatory mediators, P-MAPA enhanced the levels of pro-inflammatory cytokine IL-17 while P-MAPA+IL-12 increased IL-1β levels. The IL-12 treatment enhanced IL-17, TNF-α, IL-1β and IL-2 cytokines levels and the chemokine MIP-1α. We conclude that P-MAPA upregulated TLR2 and TLR4 signaling, possibly activating the non-canonical pathway, while attenuating the tumor immunosuppression. Combinatory therapy improved the effector T cell response, thereby contributing to eliminate tumor cells. These immunotherapies represent an additional contribution for the treatment of OC. (AU)

• FAPESP's process: 17/03441-9 - Effect of P-MAPA immunomodulator associated to Interleukin-12 on ovarian cancer: in vivo approaches involving the inflammatory process and immune system
• Grantee: Henrique Spaulonci Silveira
• Support Opportunities: Scholarships in Brazil - Master