P-MAPA activates TLR2 and TLR4 signaling while its combination with IL-12 stimulates CD4+and CD8+effector T cells in ovarian cancer

Author(s)

Silveira, Henrique Spaulonci ^[1] ; Lupi, Luiz Antonio ^[1] ; Romagnoli, Graziela Gorete ^[2] ; Kaneno, Ramon ^[2] ; Nunes, Iseu da Silva ^[3] ; Favaro, Wagner Jose ^[4] ; de Almeida Chuffa, Luiz Gustavo ^[1]

Affiliation

^[1] Sao Paulo State Univ, Inst Biosci, Dept Struct & Funct Biol, UNESP, BR-18618689 Botucatu, SP - Brazil

^[2] Sao Paulo State Univ, Inst Biosci, Dept Microbiol & Immunol, UNESP, BR-18618689 Botucatu, SP - Brazil

^[3] Farmabrasilis R&D Div, Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Dept Struct & Funct Biol, UNICAMP, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: Life Sciences; v. 254, AUG 1 2020.
• Web of Science Citations: 0

Abstract

Aims: Ovarian cancer (OC) is the most lethal gynecological malignancies and many women develop chemoresistance associated with the inflammatory process. We investigated the effects of P-MAPA and IL-12 on the inflammatory and immune responses in a chemically-induced OC model. Main methods: OCs were induced with 7,12-dimethylbenz(a)anthracene into the ovarian bursa, and the animals were given P-MAPA (5 mg/kg bw., i.p., twice a week), or IL-12 (300 ng/kg bw., i.p., one a week) for 60 days, or both P-MAPA and IL-12. Immunohistochemistry, western blot, flow cytometry, and multiplex assay were used to examine the effectiveness of immunotherapies in OC. Key findings: The combinatory therapy improved the general OC features, reducing inflammatory cells and 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 decreasing the number of regulatory T (Treg) cells. Additionally, the association of P-MAPA with IL-12 significantly increased the number of CD4+ and CD8+ T effector cells in draining lymph nodes. Regarding the inflammatory mediators, P-MAPA enhanced the levels of the pro-inflammatory cytokine IL-17 while P-MAPA+IL-12 increased the levels of IL-1 beta. Treatment with IL-12 enhanced the cytokine levels of IL-17, TNF-alpha, IL-1 beta, and IL-2 in addition to the chemokine MIP-1 alpha. Significance: We conclude that P-MAPA upregulated TLR2 and TLR4 signaling, possibly activating the non-canonical pathway, while attenuating the tumor immunosuppression. Also, the combination of P-MAPA with IL-12 improves the antitumor immunoresponse, opening a new therapeutic approach for fighting 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
• FAPESP's process: 16/03993-9 - Effect of P-MAPA immunomodulator associated to interleukin-12 on Ovarian Cancer: in vitro and in vivo approaches involving the inflammatory process and immune system
• Grantee: Luiz Gustavo de Almeida Chuffa
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/00906-6 - Melatonin and the MT1 and MT2 receptors: effects on apoptosis, cell proliferation and migratory potential of the ovarian carcinoma cells (SKOV-3 cell line)
• Grantee: Luiz Gustavo de Almeida Chuffa
• Support Opportunities: Regular Research Grants