Artículo
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 Alejandra
; Gottardo, María Florencia
; Gori, María Soledad
; Nicola Candia, Alejandro Javier; Caruso, Carla Mariana
; de Laurentiis, Andrea
; Imsen, Mercedes
; Klein, Slobodanka Mariana; Bal, Elisa Dora
; Salamone, Gabriela Veronica
; Castro, Maria G.; Seilicovich, Adriana
; Candolfi, Marianela
Fecha de publicación:
04/2017
Editorial:
Springer
Revista:
Journal Of Cancer Research And Clinical Oncology
ISSN:
0171-5216
e-ISSN:
1432-1335
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
Breast Cancer
,
Cpg
,
Dendritic Cell Vaccines
,
R848
,
Toll-Like Receptors
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Colecciones
Articulos(BIOMED)
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Articulos(CEFYBO)
Articulos de CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Articulos de CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Articulos(IMEX)
Articulos de INST.DE MEDICINA EXPERIMENTAL
Articulos de INST.DE MEDICINA EXPERIMENTAL
Articulos(INBIOMED)
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Articulos(OCA HOUSSAY)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Citación
Moreno Ayala, Mariela Alejandra; Gottardo, María Florencia; Gori, María Soledad; Nicola Candia, Alejandro Javier; Caruso, Carla Mariana; et al.; Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer; Springer; Journal Of Cancer Research And Clinical Oncology; 143; 9; 4-2017; 1713–1732
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