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- Title
Anti-metastatic immunotherapy based on mucosal administration of flagellin and immunomodulatory P10.
- Authors
Melo, Filipe M; Braga, Catarina JM; Pereira, Felipe V; Maricato, Juliana T; Origassa, Clarice ST; Souza, Mariana F; Melo, Amanda C; Silva, Priscila; Tomaz, Samanta L; Gimenes, Karina P; Scutti, Jorge AB; Juliano, Maria A; Zamboni, Dario S; Câmara, Niels O; Travassos, Luiz R; Ferreira, Luis CS; Rodrigues, Elaine G
- Abstract
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 ll-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 C57BI/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 Ml 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+PIO formulation required TLR-5, myeloid differentiation primary response gene 88 and IFN-y 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-y 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.
- Subjects
IMMUNOTHERAPY; FLAGELLIN; MELANOMA treatment; TOLL-like receptors; PARACOCCIDIOIDES brasiliensis; TUMOR antigens
- Publication
Immunology & Cell Biology, 2015, Vol 93, Issue 1, p86
- ISSN
0818-9641
- Publication type
Article
- DOI
10.1038/icb.2014.74