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Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer.
Moreno Ayala, Mariela A; Gottardo, María Florencia; Gori, María Soledad; Nicola Candia, Alejandro Javier; Caruso, Carla; De Laurentiis, Andrea; Imsen, Mercedes; Klein, Slobodanka; Bal de Kier Joffé, Elisa; Salamone, Gabriela; Castro, Maria G; Seilicovich, Adriana; Candolfi, Marianela.
Afiliação
  • Moreno Ayala MA; Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
  • Gottardo MF; Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
  • Gori MS; Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Nicola Candia AJ; Instituto de Medicina Experimental (IMEX) CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina.
  • Caruso C; Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
  • De Laurentiis A; Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
  • Imsen M; Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Klein S; Facultad de Medicina, Centro de Estudios Farmacológicos y Botánicos (CEFYBO-CONICET/UBA), Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Bal de Kier Joffé E; Cátedra de Fisiología, Facultad de Odontología, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Salamone G; Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 10, C1121ABG, Buenos Aires, Argentina.
  • Castro MG; Área Investigación, Instituto de Oncología "Ángel H. Roffo", Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Seilicovich A; Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Candolfi M; Área Investigación, Instituto de Oncología "Ángel H. Roffo", Universidad de Buenos Aires, Buenos Aires, Argentina.
J Cancer Res Clin Oncol ; 143(9): 1713-1732, 2017 Sep.
Article em En | MEDLINE | ID: mdl-28432455
PURPOSE: Since combination of Toll-like receptor (TLR) ligands could boost antitumor immunity, we evaluated the efficacy of dendritic cell (DC) vaccines upon dual activation of TLR9 and TLR7 in breast cancer models. METHODS: DCs were generated from mouse bone marrow or peripheral blood from healthy human donors and stimulated with CpG1826 (mouse TLR9 agonist), CpG2006 or IMT504 (human TLR9 agonists) and R848 (TLR7 agonist). Efficacy of antitumor vaccines was evaluated in BALB/c mice bearing metastatic mammary adenocarcinomas. RESULTS: CpG-DCs improved the survival of tumor-bearing mice, reduced the development of lung metastases and generated immunological memory. However, dual activation of TLRs impaired the efficacy of DC vaccines. In vitro, we found that R848 inhibited CpG-mediated maturation of murine DCs. A positive feedback loop in TLR9 mRNA expression was observed upon CpG stimulation that was inhibited in the presence of R848. Impaired activation of NF-κB was detected when TLR9 and TLR7 were simultaneously activated. Blockade of nitric oxide synthase (NOS) and indoleamine-pyrrole-2,3-dioxygenase (IDO) improved the activation of CpG-DCs. When we evaluated the effect of combined activation of TLR9 and TLR7 in human DCs, we found that R848 induced robust DC activation that was inhibited by TLR9 agonists. CONCLUSIONS: These observations provide insight in the biology of TLR9 and TLR7 crosstalk and suggest caution in the selection of agonists for multiple TLR stimulation. Blockade of NOS and IDO could improve the maturation of antitumor DC vaccines. R848 could prove a useful adjuvant for DC vaccines in human patients.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Adenocarcinoma / Vacinas Anticâncer / Receptor Toll-Like 9 / Receptor 7 Toll-Like Limite: Animals / Female / Humans Idioma: En Revista: J Cancer Res Clin Oncol Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Argentina País de publicação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Adenocarcinoma / Vacinas Anticâncer / Receptor Toll-Like 9 / Receptor 7 Toll-Like Limite: Animals / Female / Humans Idioma: En Revista: J Cancer Res Clin Oncol Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Argentina País de publicação: Alemanha