Mechanism of action of the peptide C36L1, a microtubule depolymerization agent, in the activation of dendritic cells and in metastatic melanoma therapy

• Grant number: 14/50723-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2015
• End date: March 31, 2018
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Luiz Rodolpho Raja Gabaglia Travassos
• Grantee: Carlos Rogerio de Figueiredo
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 15/23898-8 - Evaluation of tumour associated macrophages M1 and M2 in response to the anti-tumour C36L1 peptide, BE.EP.PD

Abstract

The effective anti-cancer immune response involves the participation of several mechanisms with the participation of antibodies, T Lymphocytes, cytokines, macrophages, with dendritic cells (DCs) as central elements, directing the basic nature of the antitumor immunity. It is widely recognized the potential of cancer rejection through the recognition of specific tumor antigens mainly by T cytotoxic Lymphocytes and NKT cells in parallel with the innate immunity represented by macrophages and natural killer (NK) cells. Immunotherapeutic protocols aim at the control of tumor growth and DCs have an essential role in this task. The great problem in cancer is the functional redirection of DCs in the tumor microenvironment, which start inducing T-regulatory Lymphocytes and immunosuppressive cytokines instead of effector antitumor cells, thus inhibiting the immune protection. The UNONEX peptides that show an antitumor activity in vivo do display immunomodulatory effects. In particular, peptide C36L1, derived from an immunoglobulin CDR that we previously described as an important agent inducing depolimerization of microtubules in melanoma cells, shows antitumor activity in vivo in a model of systemic treatment of metastatic melanoma. According to the above prediction the peptide is able to activate DCs and confer protection in vivo by adoptive transference of DCs previously stimulated ex vivo. In the development of new pharmacological agents with significant antitumor potential, the Project has as the main objective the investigation of the immunological antitumor mechanism of peptide C36L1 focusing on the capacity of activation of DCs, penetration, distribution and the molecular mechanism of signaling and functional modulation of these cells, determining the profile of the induced immune response and the study of the therapeutic treatment of murine melanoma B16F1O-Nex2 in a syngeneic system. (AU)