The antigen presenting function of DCs and their ability for inducing antitumor immunity supported the development of DC-based antitumor vaccines. We recently observed that human DCs treated with ultra low doses of antitumor chemotherapeutic agents positively modulate them to express the phenotype of mature and activated cells and stimulate the antigen presentation activity of these cells. Such concentrations was not able to destroy or induce apoptosis of tumor cells, but the DCs became more immunogenic and more susceptible to lyses by specific T lymphocytes generated in vitro. Thus, the present project was designed to evaluate whether the in vitro modulatory effects of chemotherapeutics can be also observed in vivo using the experimental model of colorectal cancer MC-38 cells. Considering that one of the schedules for antitumor chemotherapy is based on metronomic administration of antitumor agentes, that is, frequent administration of low doses of drugs, we aim to in vivo evaluate the association of DC vaccines with minimum effective doses or ultra low doses of chemotherapeutics. Since the treatment of tumor cells with low concentrations of cytotoxic drugs was able to induce transcriptional alterations in a variety of genes and such treatment upregulated the immunogenicity of tumor cells (previous results), it is necessary to evaluate whether the transfection of DCs with mRNA of tumor cells pre-treated with drugs show higher protective effect than the mRNA on non-treated tumor cells. Finally, since pre-treated tumor cells became more susceptible to specific cytotoxic T cells, we aimed to evaluate whether the phenomenon is associated with the upregulation of heat shock proteins (HSPs) by tumoral cells, one of the genes which transcription was enhanced by the pre-treatment. To achieve these goals, C57/Bl-6 mice will be subcutaneously inoculated with MC-38 cells and 10 days after they will be treated with DC vaccines, sensitized with soluble tumor antigens or tumor mRNA. Thirty days after tumor implantation, the animals will be evaluated, on their ability to induce lymphoproliferative response to tumor antigen, the ability to in vitro induce the generation of specific T lymphocytes and changes on the profile of tumor infiltrating cells.
News published in Agência FAPESP Newsletter about the scholarship: