TY - JOUR
T1 - Anti-metastatic immunotherapy based on mucosal administration of flagellin and immunomodulatory P10
AU - De Melo, Filipe M.
AU - Braga, Catarina J.M.
AU - Pereira, Felipe V.
AU - Maricato, Juliana T.
AU - Origassa, Clarice S.T.
AU - Souza, Mariana F.
AU - Melo, Amanda C.
AU - Silva, Priscila
AU - Tomaz, Samanta L.
AU - Gimenes, Karina P.
AU - Scutti, Jorge A.B.
AU - Juliano, Maria A.
AU - Zamboni, Dario S.
AU - Câmara, Niels O.
AU - Travassos, Luiz R.
AU - Ferreira, Luis C.S.
AU - Rodrigues, Elaine G.
N1 - Publisher Copyright:
© 2015 Australasian Society for Immunology Inc.
PY - 2015/1/10
Y1 - 2015/1/10
N2 - Current therapies against malignant melanoma generally fail to increase survival in most patients, and immunotherapy is a promising approach as it could reduce the dosage of toxic therapeutic drugs. In the present study, we show that an immunotherapeutic approach based on the use of the Toll-like receptor (TLR)-5 ligand flagellin (Salmonella Typhimurium FliCi) combined with the major histocompatibility complex class II-restricted P10 peptide, derived from the Paracoccidioides brasiliensis gp43 major surface protein, reduced the number of lung metastasis in a murine melanoma model. Compounds were administered intranasally into C57Bl/6 mice intravenously challenged with syngeneic B16F10-Nex2 melanoma cells, aiming at the local (pulmonary) immune response modulation. Along with a marked reduction in the number of lung nodules, a significant increase in survival was observed. The immunization regimen induced both local and systemic proinflammatory responses. Lung macrophages were polarized towards a M1 phenotype, lymph node cells, and splenocytes secreted higher interleukin-12p40 and interferon (IFN)-γ levels when re-stimulated with tumor antigens. The protective effect of the FliCi+P10 formulation required TLR-5, myeloid differentiation primary response gene 88 and IFN-γ expression, but caspase-1 knockout mice were only partially protected, suggesting that intracellular flagellin receptors are not involved with the anti-tumor effect. The immune therapy resulted in the activation of tumor-specific CD4 + T lymphocytes, which conferred protection to metastatic melanoma growth after adoptive transfer. Taken together, our results report a new immunotherapeutic approach based on TLR-5 activation and IFN-γ production capable to control the metastatic growth of B16F10-Nex2 melanoma, being a promising alternative to be associated with chemotherapeutic drugs for an effective anti-tumor responses.
AB - Current therapies against malignant melanoma generally fail to increase survival in most patients, and immunotherapy is a promising approach as it could reduce the dosage of toxic therapeutic drugs. In the present study, we show that an immunotherapeutic approach based on the use of the Toll-like receptor (TLR)-5 ligand flagellin (Salmonella Typhimurium FliCi) combined with the major histocompatibility complex class II-restricted P10 peptide, derived from the Paracoccidioides brasiliensis gp43 major surface protein, reduced the number of lung metastasis in a murine melanoma model. Compounds were administered intranasally into C57Bl/6 mice intravenously challenged with syngeneic B16F10-Nex2 melanoma cells, aiming at the local (pulmonary) immune response modulation. Along with a marked reduction in the number of lung nodules, a significant increase in survival was observed. The immunization regimen induced both local and systemic proinflammatory responses. Lung macrophages were polarized towards a M1 phenotype, lymph node cells, and splenocytes secreted higher interleukin-12p40 and interferon (IFN)-γ levels when re-stimulated with tumor antigens. The protective effect of the FliCi+P10 formulation required TLR-5, myeloid differentiation primary response gene 88 and IFN-γ expression, but caspase-1 knockout mice were only partially protected, suggesting that intracellular flagellin receptors are not involved with the anti-tumor effect. The immune therapy resulted in the activation of tumor-specific CD4 + T lymphocytes, which conferred protection to metastatic melanoma growth after adoptive transfer. Taken together, our results report a new immunotherapeutic approach based on TLR-5 activation and IFN-γ production capable to control the metastatic growth of B16F10-Nex2 melanoma, being a promising alternative to be associated with chemotherapeutic drugs for an effective anti-tumor responses.
UR - http://www.scopus.com/inward/record.url?scp=84920530402&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920530402&partnerID=8YFLogxK
U2 - 10.1038/icb.2014.74
DO - 10.1038/icb.2014.74
M3 - Article
C2 - 25223833
AN - SCOPUS:84920530402
SN - 0818-9641
VL - 93
SP - 86
EP - 98
JO - Immunology and Cell Biology
JF - Immunology and Cell Biology
IS - 1
ER -