X-TAM · Dissecting Cross-Regulatory Interplays in Tumor-Associated Macrophages

Macrophages are specialized innate immune cells with central roles in homeostasis and disease. Uponexposure to micro-environmental stimuli, these cells can adopt a variety of phenotypes ranging from immunestimulation and cytotoxicity to immune suppression and tissue repair. Dynamic transitions between thesefunctional properties in response to tumor signals is thought to underlie the generally pathogenic role ofmacrophages in cancer. At the same time, macrophage plasticity could be exploited to therapeuticallyreprogram 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, transcriptionaland post-transcriptional landscape of macrophages. However, these studies do not take into consideration theinterplay that these stimuli may have when present at the same time.This project aims to elucidate how macrophages integrate incoherent environmental stimuli at the genomiclevel, and translate them into context-specific gene expression programs. Because concomitant activation ofantagonistic pro-inflammatory and anti-inflammatory pathways is almost invariably observed in cancer, wepropose 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 functionalscreenings 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 theimmune system, and deliver innovative cell and gene therapy strategies to manipulate the behaviour ofmacrophages in cancer.