Macrophage Boost Therapy
Partners : COL, OCR, Univ. 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 also 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 3 dimensional cell culture system allowing to mimic tumor complexity. We will then move to an ex vivo tumor explants culture system. Finally, we will finish with ex and in vivo experiment by using explant, and dog patients.