Immuno-oncology is an emerging field that is revolutionizing the treatment of cancer. Although most immunomodulatory strategies have focused on increasing T cell response, there has been a recent increase in the interest in the natural killer (NK) cell compartment. Clinical responses to NK cell-based adoptive immunotherapy, however, were thwarted by the profound immunosuppression induced by the tumor microenvironment, particularly severe in the context of solid tumors. Tumor-associated macrophages (TAMs) play a prominent role in suppressor modulation of the tumor microenvironment, and it has been shown that these cells are involved in the inactivation of NK cells stimulated in vitro and transferred to cancer patients. The interaction between TAMs and NK cells may therefore be a prospective therapeutic target for enhancing cancer cell therapies, and molecules having both of these cells as targets have the potential to be immunoadjuvant agents. It has been demonstrated that biomolecules of scorpion and spider venoms have chemotherapeutic and immunomodulatory effects. Recent results from our research group have shown that the venom of the spider Phoneutria nigriventer (PnV) (Ctenidae, Araneomorphae) had a cytotoxic effect on tumor cells, in vitro and in vivo. However, while in the in vitro model the venom reduced cell viability by about 25%, the final volume of the xenogeneic tumor developed in immunocompetent mice treated with PnV was approximately 90% lower than in the control (untreated) animals. These data lead to the hypothesis that the venom could act in the tumor microenvironment, contributing to combat the tumor through immunomodulation, specifically the innate immunity, since the xenographic model lacks adaptive response. In fact, preliminary data indicated a modulatory role of venom in macrophages, increasing phagocytic activity and the infiltration of these cells in a tumor implanted in mice treated with PnV; also, there was an increase in the proportion of NK cells isolated from the spleen of chronically treated animals with venom, compared to control animals. Therefore, corroborating with the hypothesis put forward, the venom seems to stimulate the innate response mediated by macrophages and NK cells. Considering that TAMs are suppressor cells possibly responsible for the inactivation of NK cells in the tumor environment, it is possible that the activation of both cells by components of the venom induces a more effective innate immune response against the neoplastic cells. The present study will use in vitro models (2D and 3D) to characterize the effects of PnV on NK cells and macrophages. In vitro models will also be used for high throughput screening to identify the peptide (or peptides) isolated from the venom, responsible for immunomodulatory effects. Finally, the present project proposes to evaluate, in a preclinical model, the potential of chronic therapy through systemic injection of the active peptide, or chronic cellular therapy with macrophages and NK cells modulated ex vivo by the peptide and transferred adoptively to animals with xenogeneic and syngeneic tumors. In addition, an internship period abroad (BEPE - Attached Work Plan) is being proposed to characterize the mechanisms of venom in macrophages. The experience with the group abroad (Thomas Jefferson University, Philadelphia, US) will contribute to the development of this project and will also be very relevant for the formation of the student and for the incorporation of new methods by the research group in Brazil. The elucidation of these questions will be important in the development of a potential therapy using peptide isolated from the venom as immunoadjuvant.
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