Author(s):
Silveira, Henrique Spaulonci [UNESP] ; Lupi, Luiz Antonio [UNESP] ; Romagnoli, Graziela Gorete [UNESP] ; Kaneno, Ramon [UNESP] ; da Silva Nunes, Iseu ; Fávaro, Wagner José ; de Almeida Chuffa, Luiz Gustavo [UNESP]
Date: 2020
Persistent ID: http://hdl.handle.net/11449/200442
Origin: Oasisbr
Subject(s): IL-12; Immune cells; Inflammation; Ovarian cancer; P-MAPA; TLR; IL-12; IL-12; Immune cells; Immune cells; Inflammation; Inflammation; Ovarian cancer; Ovarian cancer; P-MAPA; P-MAPA; TLR; TLR
Description
Made available in DSpace on 2020-12-12T02:06:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-08-01
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
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.
Department of Structural and Functional Biology UNESP - São Paulo State University Institute of Biosciences
Department of Microbiology and Immunology UNESP - São Paulo State University Institute of Biosciences
Farmabrasilis R&D Division
Department of Structural and Functional Biology UNICAMP - University of Campinas
Department of Structural and Functional Biology UNESP - São Paulo State University Institute of Biosciences
Department of Microbiology and Immunology UNESP - São Paulo State University Institute of Biosciences
CAPES: 0708/2018
FAPESP: 2016/03993-9
FAPESP: 2017/03441-9
FAPESP: 2019/00906-6
