MetaMacNiche · Unravelling the cell-cell circuits underlying the functional reprogramming of KCs and TAMs during liver metastasis

Unravelling the cell-cell circuits underlying the functional reprogramming of KCs and TAMs during liver metastasis

The liver is a highly vascularized organ due to its major role in filtering blood. Because of this, the liver is also one of the main site of metastatic dissemination for several cancers. The most common one is colorectal cancer, with up to 50% of patients developing liver metastases. The primary treatment for liver metastasis is surgery but, if metastases are too spread, surgery is not an option anymore. The 21st century has marked a boomed in immunotherapy, especially in cancer. However, previous research have highlighted that metastatic dissemination to the liver impairs systemic immune responses, making patients less responsive to immunotherapy. Macrophages are the most abundant immune population in many cancers. Kupffer cells are the resident macrophages of the liver are the first cells to interact with metastatic cells due to their location in the liver sinusoids. Additionally, monocyte-derived macrophages are also rapidly recruited as metastatic cells are spreading to the liver, and will constitute the tumor-associated macrophages (TAMs). The distinct role of Kupffer cells and TAMs in metastatic spreading and anti-cancer immune response have been studied in the past but showed conflicting results. Macrophages in cancer do not form a homogenous cell populations and can be wired to perform various functions, either promoting or inhibiting anti-cancer immunity. Our group, and other have shown that macrophage function is dictated not only by intrinsic factor, but also by signals delivered by their surrounding cells (ie fibroblasts, endothelial cells, cancer cells…), defining the macrophage niche. Using unique tracking tools developed in our lab, as well as cutting-edge omics and spatial technologies, this project aims at deciphering the cross-talk between macrophages and their niche, the consequences on macrophage polarization and immunotherapy response, as well as identifying novel therapeutic targets that can modulate tumor macrophage activation.

Data: CORDIS, © European Union