Anti-metastatic immunotherapy based on mucosal administration of flagellin and immunomodulatory P10.

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 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.

DOI: 10.1038/icb.2014.74

Cite this paper

@article{Melo2015AntimetastaticIB, title={Anti-metastatic immunotherapy based on mucosal administration of flagellin and immunomodulatory P10.}, author={Filipe M de Melo and Catarina J. M. Braga and Felipe Valença Pereira and Juliana Terzi Maricato and Clarice Silvia Taemi Origassa and Mariana Fernandes de Souza and Amanda C. L. Melo and Priscila Sabino da Silva and Samanta Lopes Tomaz and Karina P. Gimenes and Jorge A. B. Scutti and Maria Aparecida Juliano and Dario S Zamboni and Niels O. S. C{\^a}mara and Luiz R Travassos and Lu{\'i}s Carlos de Souza Ferreira and Elaine Guadelupe Rodrigues}, journal={Immunology and cell biology}, year={2015}, volume={93 1}, pages={86-98} }