Une nouvelle stratégie d’immunothérapie : cibler directement des immunostimulants à la surface des cellules tumorales par ligation bio-orthogonale

Abstract : Cancer immunotherapy uses the patient's own immune system to fight cancer. In this research project, we propose a new strategy for immunotherapy: binding immunostimulants in situ to the tumor cell surface using bio-orthogonal chemistry. For that purpose we use the particular and active metabolism of tumor cells to introduce by metabolic glycoengineering into their cell surface glycans, azido sugars capable of binding many different immunostimulants carrying adequate reactive groups. The biorthogonal chemistry allowing this specific ligation is based on the use of two mutually reactive groups both naturally absent from biological systems and which can be coupled selectively and very quickly in conditions totally compatible with living organisms. Our choice of immunostimulants consists, on one hand, of CpG oligonucleotides (powerful general immunostimulants) and on the other hand of β-glucans (phagocytosis stimulants used in combination with therapeutic antibodies without causing strong cytokine secretion). We determined the best conditions for the introduction of azido sugars into cell glycans of different tumor models and tried different biorthogonal groups and reaction conditions to obtain the best immunostimulant coupling to the surface of various tumor cell lines. Then, we performed in vitro immunological tests and in vivo studies in mice in order to validate the effect of the association between immunostimulants and tumor cells on the immune response against tumors. Thereby, we observed on a group of mice, reduced tumor growth when the strong immunostimulant CpG was fixed onto tumor cell surface.
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Aline Mongis. Une nouvelle stratégie d’immunothérapie : cibler directement des immunostimulants à la surface des cellules tumorales par ligation bio-orthogonale. Biologie cellulaire. Université d'Orléans, 2017. Français. ⟨NNT : 2017ORLE2008⟩. ⟨tel-01713120⟩

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