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

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-1β. Treatment with IL-12 enhanced the cytokine levels of IL-17, TNF-α, IL-1β, and IL-2 in addition to the chemokine MIP-1α.

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.

• Authors: Henrique Spaulonci Silveira, Luiz Antonio Lupi, Graziela Gorete Romagnoli, Ramon Kaneno, Iseu da Silva Nunes, Wagner José Fávaro, Luiz Gustavo de Almeida Chuffa
• Journal: Life sciences (Life Sci) Vol. 254 Pg. 117786 (Aug 01 2020) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 32433918 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Chemokine CCL3
• Cytokines
• Linoleic Acids
• Oleic Acids
• P-mapa
• Ticam1 protein, rat
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Interleukin-12
• 9,10-Dimethyl-1,2-benzanthracene

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Adaptor Proteins, Vesicular Transport (metabolism)
• Adipocytes (drug effects)
• Animals
• CD4-Positive T-Lymphocytes (drug effects)
• CD8-Positive T-Lymphocytes (drug effects, metabolism)
• Chemokine CCL3 (metabolism)
• Cytokines (metabolism)
• Drug Synergism
• Female
• Inflammation (drug therapy)
• Interleukin-12 (pharmacology, therapeutic use)
• Linoleic Acids (pharmacology, therapeutic use)
• Oleic Acids (pharmacology, therapeutic use)
• Ovarian Neoplasms (chemically induced, drug therapy, metabolism)
• Rats
• T-Lymphocytes, Regulatory (drug effects)
• Toll-Like Receptor 2 (metabolism)
• Toll-Like Receptor 4 (metabolism)