Autor(es): Silveira, Henrique Spaulonci [UNESP]
Data: 2020
Identificador Persistente: http://hdl.handle.net/11449/192087
Origem: Oasisbr
Assunto(s): Câncer de ovário; P-MAPA; IL-12; TLR; inflamação; Células imunes; Ovarian cancer; Immune cells; Inflammation; Câncer de ovário; Câncer de ovário; P-MAPA; P-MAPA; IL-12; IL-12; TLR; TLR; inflamação; inflamação; Células imunes; Células imunes; Ovarian cancer; Ovarian cancer; Immune cells; Immune cells; Inflammation; Inflammation
Submitted by Henrique Spaulonci Silveira (henrique.spaulonci@unesp.br) on 2020-04-02T14:10:49Z No. of bitstreams: 1 Dissertação MESTRADO Henrique Spaulonci Silveira.pdf: 3355123 bytes, checksum: df19a5a3baf8c5cb71442e31a2c1842c (MD5)
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Submitted by Henrique Spaulonci Silveira (henrique.spaulonci@unesp.br) on 2020-04-02T14:10:49Z No. of bitstreams: 1 Dissertação MESTRADO Henrique Spaulonci Silveira.pdf: 3355123 bytes, checksum: df19a5a3baf8c5cb71442e31a2c1842c (MD5)
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
O câncer de ovário (CO) é a segunda mais letal de todas as neoplasias ginecológicas e muitas mulheres adquirem quimiorresistência associada ao processo inflamatório. A interleucina-12 (IL-12) é responsável pela resposta inflamatória T helper 1 (Th1) e o agregado proteico de fosfolinoleato de amônio e magnésio e anidrido palmitoleato (P-MAPA) atua como um agente imunoestimulador em cânceres agressivos. Este estudo investigou os tratamentos funcionais com P-MAPA e IL-12 no processo inflamatório e nas células imunes relacionadas ao CO em um modelo in vivo. O CO foi induzido quimicamente com 7,12-dimetilbenz(a)antraceno (DMBA) diretamente na bolsa ovariana e, após o desenvolvimento dos tumores, os animais receberam P-MAPA, IL-12 ou P-MAPA combinado com IL-12. A terapia combinatória melhorou as características histológicas características do CO, contribuindo para a redução das células inflamatórias, acúmulo de adipócitos, além de apresentar um tecido mole e móvel, sem aderências e implantes peritoneais. O tratamento com P-MAPA aumentou os níveis de TLR2, TLR4 e TRIF nos OCs, enquanto diminuiu o número de células T reguladoras (Treg) (CD4+ CD25+/FoxP-3+ e CD8+ FoxP-3+). Além disso, a associação de P-MAPA com IL-12 estimulou significativamente as células T CD4+ e CD8+ efetoras nos linfonodos drenantes. Em relação aos mediadores inflamatórios, o P-MAPA aumentou o nível da citocina pró-inflamatória IL-17, enquanto o P-MAPA+IL-12 aumentou os níveis de IL-1β. O tratamento com IL-12 aumentou os níveis das citocinas IL-17, TNF-α, IL-1β e IL-2 e a quimiocina MIP-1α. Concluímos que o P-MAPA regulou positivamente a sinalização de TLR2 e TLR4, possivelmente ativando a via não-canônica, estimulando a resposta imune frente ao tumor. A terapia combinada melhorou a resposta efetiva das células T, contribuindo assim para eliminar as células tumorais. Essas imunoterapias representam uma contribuição adicional para o tratamento da CO.
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.
FAPESP: 2017/03441-9
CAPES: 0708/2018
