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Avaliação de um novo protocolo de imunoterapia com células dendríticas no tratamento de tumores experimentais de mama induzido com células 4T1Tumor de mama.Imunoterapia.Células dendríticas.Breast cancer.Immunotherapy.Dendritic cell.MedicinaIntrodução: O tumor é a segunda causa de óbitos em todo o mundo, cerca de 9,6 milhões em 2018. A imunoterapia com células dendríticas no tratamento do tumor objetiva ativar a resposta imune para que sejam capazes de eliminar células neoplásicas. O presente estudo teve por objetivo avaliar o perfil de resposta imune induzido por células dendríticas submetidas à diferentes protocolos de maturação no baço e microambiente tumoral de camundongos com tumor de mama experimental. Materiais e métodos: Para este estudo, células pluripotentes da medula óssea de camundongos Balb/c fêmeas foram diferenciadas por meio do estímulo com fator estimulador de colônias de granulócitos e macrófagos (GM-CSF) e interleucina-4 (IL-4). Posteriormente, estas células foram submetidas a dois diferentes protocolos de maturação. No protocolo DCs, as células dendríticas foram estimuladas com TNF-α e lisado tumoral. No protocolo LPSDCs, as células dendríticas foram estimuladas com TNF-α, lipopolissacarídeo e lisado tumoral. As células DCs e LPSDCs foram utilizadas para imunoterapia de camundongos Balb/c fêmeas com tumor de mama experimental induzido com células de linhagem 4T1 (n= 10 animais por grupo). Após o período experimental, células esplênicas e intratumorais foram coletadas e avaliadas por meio da citometria de fluxo. Resultados: Em nosso estudo observamos as vacinas DCs e LPSDCs reduzem o volume tumoral tumoral (p<0,0001) quando comparados aos camundongos com tumor de mama não tratados. Além disso, observamos que a vacina LPSDCs induz um aumento do percentual de células T auxiliares CD3+ CD4+ esplênicas e intratumorais quando comparada aos grupos WT (p<0,001) e Tumor (p<0,0001). Ambas as vacinas aumentaram a produção de IFN-γ no microambiente tumoral (p<0,0001) quando comparados ao grupo Tumor. O tratamento de camundongos com tumor de mama com a vacina LPSDCs induziu uma redução significativa do percentual de células T reguladoras e macrófagos no microambiente tumoral quando comparados ao grupo Tumor (p<0,0001) e uma maior porcentagem de células NK CD335+ quando comparado aos grupos Tumor (p=0,0201) e DCs (p=0,0001). Conclusão: este estudo experimental demonstra que respostas imunes in vivo são induzidas por meio da imunoterapia com células dendríticas, sendo que o estímulo adicional com lipopolissacarídeo induz o aumento da infiltração de células imunes com atividade antitumoral e redução de células imunossupressoras no microambiente tumoral.Introduction: Cancer is the second cause of death worldwide, about 9.6 million in 2018. Immunotherapy with dendritic cells for cancer patients aims to activate the immune response to be eliminate neoplastic cells. Our study aimed to evaluate the immune response profile induced by dendritic cells submitted to different maturation protocols in the spleen and tumor microenvironment of mice with experimental breast cancer. Materials and methods: For this study, bone marrow pluripotent cells of female Balb/c mice were differentiated by stimuly with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Subsequently, these cells were submitted to two different maturation protocols. In the DCs protocol, dendritic cells were stimulated with TNF-α and tumor lysate. In the LPSDCs protocol, dendritic cells were stimulated with TNF-α, lipopolysaccharide and tumor lysate. DCs and LPSDCs cells were used for immunotherapy of female Balb/c mice with experimental breast cancer induced with 4T1 lineage cells (n= 10 animals each group). After the experimental period, splenic and intratumoral cells were collected and evaluated by flow cytometry. Results: In our study we observed that DCs and LPSDCs reduce the tumor growth rate (p<0.0001) when compared to the untreated breast cancer mice. In addition, we observed that the LPSDCs vaccine induces an increase in the percentage of splenic and intratumoral CD3+ CD4+ T helper cells when compared to the WT (p<0.001) and Tumor (p<0.0001) groups. Both vaccines increased the production of IFN-γ in the tumor microenvironment (p <0.0001) when compared to the Tumor group. The treatment with the LPSDCs vaccine induced a significant reduction in the percentage of regulatory T cells and macrophages in the tumor microenvironment when compared to the Tumor group (p <0.0001) and a higher percentage of CD335+ NK cells when compared to Tumor (p=0.0201) and DCs (p=0.0001) groups. Conclusion: This experimental study demonstrates that in vivo immune responses are induced by immunotherapy with dendritic cells, and additional stimulation with lipopolysaccharide induces increased infiltration of immune cells with antitumor activity and reduction of immunosuppressive cells in the tumor microenvironment.Fundação de Amparo à Pesquisa do Estado de Minas GeraisUniversidade Federal do Triângulo MineiroConselho Nacional de Desenvolvimento Científico e TecnológicoUniversidade Federal do Triângulo MineiroInstituto de Ciências da Saúde - ICS::Programa de Pós-Graduação em Ciências da SaúdeBrasilUFTMPrograma de Pós-Graduação em Ciências da SaúdeMICHELIN, Márcia Antoniazi11828808865http://lattes.cnpq.br/2599409028588669MURTA, Eddie Fernando Candido47668032649http://lattes.cnpq.br/5724192420139830LOPES, Angela Maria Moed2019-09-02T18:52:47Z2019-07-03info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfapplication/pdfLOPES, Angela Maria Moed. 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Blood, v. 107, n. 9, p. 3600–3608, 2006.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFTMinstname:Universidade Federal do Triangulo Mineiro (UFTM)instacron:UFTM2019-09-03T04:00:23Zoai:bdtd.uftm.edu.br:tede/849Biblioteca Digital de Teses e Dissertaçõeshttp://bdtd.uftm.edu.br/PUBhttp://bdtd.uftm.edu.br/oai/requestbdtd@uftm.edu.br||bdtd@uftm.edu.bropendoar:2024-04-24T09:59:37.906910Biblioteca Digital de Teses e Dissertações da UFTM - Universidade Federal do Triangulo Mineiro (UFTM)false
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