X-TAM SIGNED

Project "X-TAM" data sheet

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 Project objective

Macrophages are specialized innate immune cells with central roles in homeostasis and disease. Upon exposure to micro-environmental stimuli, these cells can adopt a variety of phenotypes ranging from immune stimulation and cytotoxicity to immune suppression and tissue repair. Dynamic transitions between these functional properties in response to tumor signals is thought to underlie the generally pathogenic role of macrophages in cancer. At the same time, macrophage plasticity could be exploited to therapeutically reprogram the phenotype of these cells by pharmacological, cell and gene therapy approaches. Current models of macrophage activation are based on in-depth analyses of the effect of individual stimuli, such as pro- or anti-inflammatory cytokines, on the biochemical, cell biological, epigenetic, transcriptional and post-transcriptional landscape of macrophages. However, these studies do not take into consideration the interplay that these stimuli may have when present at the same time. This project aims to elucidate how macrophages integrate incoherent environmental stimuli at the genomic level, and translate them into context-specific gene expression programs. Because concomitant activation of antagonistic pro-inflammatory and anti-inflammatory pathways is almost invariably observed in cancer, we propose that these interplays are critical determinants of the biology of tumor-associated macrophages. Our approach integrates cutting-edge genomics and computational modelling with in vitro functional screenings and in vivo manipulation of macrophages, building on uniquely available gene therapy platforms. Successful completion of this project will generate widely exportable paradigms of gene regulation in the immune system, and deliver innovative cell and gene therapy strategies to manipulate the behaviour of macrophages in cancer.

 Publications