MacBeth : Macrophage Boost Therapy
Supports : Inserm, INCA, I-Site, Région Hauts de France
Partners : COL, OCR, Canther, Univerty Mainz (Dr. A. Vigouroux)
The project deals with the development of a therapeutic strategy allowing macrophages activation within tumor. The immunosuppressive environment created by tumor cells orients macrophages phenotype toward a pro-tumor phenotype. They will then participate to tumor growth by acting directly on tumor cells but also by suppressing T lymphocytes cytotoxic response. They are a key component of tumor environment. The challenge is to find a way to counter this immunosuppression and reactivate macrophages. Our strategy is to use a proproteins convertases inhibitor combined with a TLR receptor ligand to reactivate tumor associated macrophages in glioma. In this context, we have recently demonstrated that macrophages activation could be modulated via an enzyme called proprotein convertase 1/3 (PC1/3). Inhibition of this enzyme triggers an abundant secretion of immune factors and orients macrophages toward a M1 pro-inflammatory phenotype. Activation of these macrophages is even more important when they are stimulated with TLRs ligands. These macrophages also secret anti-tumor factors effective against glioma cells and act on their invasion. Then our aim is to develop a therapeutic strategy to reactivate macrophages via PCs inhibitor combined with a TLR receptor ligand. These studies will be led, in a first time in vitro to test the different possible combinations, by using a 3Dcell culture system as well as organoids allowing to mimic tumor complexity. For that purpose, we developed 3D organoids mixed with macrophages including embryonic stem cells for blood vessels development. We will then move to an ex vivo tumor explants culture system. We will finish with ex and in vivo experiment by using explant, and dog patients. In the same time , we are initiating a new therapeutic strategy including Macrophage CAR associated with PC1/3 inhibitor drug delivery at the tumor environment.
- Lansac G, Dong W, Dubois C, Ben Larbi N, Carlos Alfonso, Fournier I, Salzet M, Day R Lipopolysaccharide-mediated regulation of proprotein convertases in the rat spleen: Induction of neuroendocrine-associated convertases and neuropeptides and their potential role in antibacterial activity. . J. Neuroimmunol (2006), 171(1-2):57-71
- Refaie S, Gagnon S, Gagnon H, Desjardins R, D’Orléans-Juste P, Zhu X, Steiner DF, Seidah NG, Lazure C, Salzet M, Day R Disruption of PC1/3 expression in mice causes innate immune defects and uncontrolled cytokine J Biol Chem. (2012) 287(18):14703-17
- Duhamel M, Rodet F, Delhem N, Vanden Abeele F, Kobeissy F, Nataf S, Pays L, Desjardins R, Gagnon H, Wisztorski M, Fournier I, Day R, Salzet M. Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study.Mol Cell Proteomics. (2015) 14(11):2857-77. (Journal cover)
- Duhamel M, Rodet F, Murgoci AN, Desjardins R, Gagnon H, Wisztorski M, Fournier I, Day R, Salzet M The proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways Sci Rep. (2016) 6:1936 Duhamel M., Rodet F., Murgoci A.N., Wiztorski M., Day R., Fournier i., Salzet M. Proprotein convertase 1/3 inhibited macrophages: a ovel therpautic based on drone macrophages. EuPA Open Proteomics 11, 20-22
- Duhamel M, Rose M, Rodet F, Murgoci AN, Zografidou L, Régnier-Vigouroux A, Abeele FV, Kobeissy F, Nataf S, Pays L, Wisztorski M, Cizkova D, Fournier I, Salzet M (2018) Paclitaxel Treatment and Proprotein Convertase 1/3 (PC1/3) Knockdown in Macrophages is a Promising Antiglioma Strategy as Revealed by Proteomics and Cytotoxicity Studies.. Molecular and Cellular Proteomics 17(6):1126-1143
- Rodet F, Capuz A, Hara T, van Meel R, Duhamel M, Rose M, Raffo-Romero A, Fournier I, Salzet M Deciphering molecular consequences of the proprotein convertase 1/3 inhibition in macrophages for application in anti-tumour immunotherapy.J Biotechnol. 2018 Sep 20;282:80-85
- Rodet F, Capuz A, Ozcan BA, Le Beillan R, Raffo-Romero A, Kobeissy F, Duhamel M, Salzet M PC1/3 KD Macrophages Exhibit Resistance to the Inhibitory Effect of IL-10 and a Higher TLR4 Activation Rate, Leading to an Anti-Tumoral Phenotype.Cells. 2019 Nov 22;8(12). pii: E1490
- Rose M, Duhamel M, Aboulouard S, Kobeissy F, Le Rhun E, Desmons A, Tierny D, Fournier I, Rodet F, Salzet M The role of a proprotein convertases inhibitor in reactivation of tumor associated macrophages and inhibition of glioma growth. Molecular Therapy oncolytics (In press)
ESCULAPE : Engineered System to treat Cancer Using Long distance Actuation to Pilot Exosomes
Supports : I-Site, Région Hauts de France
Partners : Oncovet Clinical Research, OCR, IEMN
Exosomes are small single lipid membrane entity secreted by eukayotic and prokaryotic cells and play an important role in intercellular signalling and nutrient transport 10. These extracellular vesicles have attracted researchers because they act as shuttle agents to transfer biomolecules/drugs between cells. Recent studies have shown the application of exosomes in tumour therapy. The ESCULAPE project is dedicated to the development of an innovative technique to treat cancer tumours using physical fields to remotely pilot exosomes isolated from macrophages.
- Murgoci A-N, CizkovA D, Majerova P, Petovova E, Mevecky L, Fournier I, Salzet M (2018) Brain-Cortex Microglia-Derived Exosomes: Nanoparticles for Glioma Therapy ChemPhysChem 22;19(10):1205-1214.
- Murgoci A-N, Mallah K, Aboulouard S, Lefebvre C, Kobeissy F, Fournier I, Cizek M, Cizkova D, Salzet M The origin of microglia determines the content of exosomes and biological function. Journal of Extracellular Vesicles 9 (1), 1727637
- Murgoci A-N,Cardon T, Aboulouard S, Duhamel M, Fournier I, Cizkova D, Salzet M Reference and Ghost proteins identification in Rat C6 glioma extracellular vesicles. IScience (In press)