Cancer is a multifactorial disease, involving a complex mechanism. In the last decade, the evasion of the immune response has been recognized as an important feature of tumor development. Since the immune system is responsible for recognizing and eliminating neoplastic cells, the development of solid tumors would therefore occur through a failure in that system. On the other hand, it has been shown that inflammation contributes to the development of tumors, generating a paradox about the role of the immune system in cancer. Among the major cells involved in the innate immune system activation are macrophages. These cells have been classified in the types M1 and M2 (although this polarization is a simplistic concept and there is in fact a complex phenotypic spectrum) and they present a complex relation with respect to the prognosis of tumors and treatments are already described in the literature using immunomodulation of macrophages, with activation, deletion or reprogramming of these cells. Recent studies in our group have demonstrated that Phoneutria nigriventer spider venom (PnV) led to the death of tumor cells in an in vitro model, in addition to the reduction or eradication of the development of gliomas in a xenographic tumor developed in mice. However, while in vitro the venom reduced cell viability by about 20%, the final volume of the tumor developed in mice treated with PnV was about 90% lower than in control (untreated) animals. Therefore, although there may be a direct cytotoxic effect of venom on tumor cells implanted in mice, this effect does not justify the observed tumor reduction rates. These results led to the hypothesis that the venom could be acting in the tumor microenvironment, contributing to combat the tumor through immunomodulation. Since immunodeficient mice lack an adaptive immune response, the venom could modulate the innate immune response mediated by macrophages. Corroborating with the hypothesis, preliminary in vitro studies indicated a modulatory role of venom in macrophages, increasing their phagocytic activity, as well as the expression of class II molecules of the major histocompatibility complex (MHC II) and costimulatory molecules. Therefore, the present work aims to investigate the in vitro effect of PnV on the activation of differentiated macrophages from the bone marrow, through a phenotypic and functional analysis of these cells, starting the study on a possible immunomodulatory role of the venom. It is also our objective to identify the peptide isolated from the venom responsible for such effects. In addition, the present project intends to request a BEPE (attached work plan), which aims to clarify the effects of PnV and its isolated peptides on Tumor Associated Macrophages (TAMs), through collaboration with the research group of Professor Mikael Karlsson of the Karolinska Institute (Stockholm, Sweden), who is currently reference in the study of the subject. The work will therefore contribute to the elucidation of relevant issues, which may result in the development of a new therapy using the peptide isolated from the venom as immunoadjuvant.
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