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Assessment of response to oncolytic viral therapy in immunogenic tumors: the role of extracellular vesicles in the therapeutic outcome

Abstract

Malignant tumors can be defined as microenvironments composed by different cell types that interact with each other, dictating the natural history of the disease and the response to treatment. This cellular interaction is mediated not only by soluble factors, but also by extracellular vesicles (EVs). EVs are spherical nanostructures, secreted by many cell types, which play an important role in tumor progression. Its effects are mediated by the horizontal transfer of macromolecules to recipient tumoral or stromal cells, altering the functionality of these cells. We recently demonstrated that EVs secreted by melanoma during chemotherapy induce a nuclear reprogramming in tumor cells and also the acquisition of an anti-inflammatory phenotype by macrophages, leading to the recurrence of these tumors. On the other hand, these EVs can induce a pro-inflammatory and anti-tumoral phenotype in macrophages during radiotherapy, indicating that this differential action is dependent on the type of treatment. In this sense, the oncolytic viral therapy is a therapeutic modality that has been explored for the treatment of neoplasms; however, studies on the action of EVs in this context are still elusive. Thus, our proposal aims to evaluate the effect of EVs secreted during the oncolytic viral therapy in immunogenic solid tumors. To this end, the biological action of these nanostructures on the phenotype of tumoral and infiltrating immune cells will be investigated, as well as the content of vesicular microRNA. Our hypothesis is that the analysis of the content and biological action of EVs secreted during the therapeutic period constitutes a potential predictive factor of response. (AU)