Abstract
Macrophages can differentiate into several distinct subtypes in response to external stimuli : mainly in called “classic” M1 macrophages and in “alternative” M2 macrophages. Within the tumor microenvironment, macrophages represent the majority cell population and can account for nearly half of the tumor mass. This massive recruitment of macrophages, also called TAM (tumor associated macrophages) is associated with a poor prognosis in many cancers such as glioblastoma. Indeed, numerous studies have established that macrophages play a key role in the evolution of glioblastoma through their numerous pro-tumoral functions. Interestingly, the macrophage phenotype has been shown to change during tumorigenesis. Thus, in early tumors, the macrophages have an M1 inflammatory and tumoricidal “classic” phenotype. These macrophages are cytotoxic, phagocytic and promote antigen presentation while limiting tumor growth. However, as the tumor progresses and becomes more established, the macrophages shift towards an "alternative" M2 phenotype that promote a deleterious immunosuppressive microenvironment. These macrophages exhibit a pro-tumoral phenotype that promotes angiogenesis and inhibits T-cell activation. Recently, repolarization of M2 macrophages to M1 has become a new therapeutic strategy. The molecular mechanisms leading to M1 or M2 polarization have been widely studied in different contexts, but the role played by the cytosolic nucleic acid pathway cGAS-STING on macrophage polarization remains poorly explored. However, this pathway appears to play a determining role in the inflammation associated with cancer. This CIFRE thesis project studied the effect of cytosolic nucleic acids and in particular double strands DNA on macrophage polarization. The interactions between tumor cells and macrophages were also explored in a model of glioblastoma. For this purpose, two different models, in vitro (developed within the team of Dr. Nadine Laguette at IGH) and in vivo on zebrafish embryos (developed within the company AZELEAD) were combined. The project was structured around the following research axes : Characterization of the impact of nucleic acids and exploration of the cGAS-STING signaling pathway on macrophage polarization in vitro. Establishment of a zebrafish model to study and model in 3D the tumor microenvironment associated with glioblastoma and characterization of macrophages-cancer cells interactions in vivo. Finally, this work explored the effect of cGAS on the tumorigenesis, recruitment and polarization of macrophages in vivo.