3106269078

Cancer is a multifactonal disease dimcult to treat. Indeed, tumor cells have acąuired mutations allowing them, among other things, to evade from the immune system. This immune tolerance is then extremely hard to break. Oncolytic virotherapy is a way increasingly studied in order to induce a pro-inflammatory State at the tumor site by lysing cancer cells. This allows the recognition of tumor antigens in the presence of appropriate activation signals to mount an antitumor immune response. The overall objective of this project is to characterize the therapeutic immunomodulation induced by various mutants of vesicular stomatitis virus and how to potentiate the recognition of cancer cells by the immune system in the murine melanoma model B16gp33. To enable the study of immune mechanisms involved in viral oncolysis, we characterized different mutants of the envelope glycoprotein and the matrix protein of VSV which have various oncolytic properties in melanoma cells. We then established that cytopathic viruses induce a better immune response against the gp33 exogenous epitope while the attenuated mutant Mmsir allows a wider tolerance break with the establishment of an immune response against a variety of tumor antigens. We also demonstrated that, although not influencing virotherapy, a transient inhibition of the complement system contributes to antitumor immunomodulation through the action of NK cells. Globally, this thesis focuses on the ability to influence the immune system to recognize tumor cells by the action of active agents such as VSV or by directly targeting players of the immune system.