Chemokines orchestrate immune response especially by leucocytes mobilization. Myeloidcells, notably monocytes, are involved in inflammation and cancer development. Indeedmonocyte-derived cells and macrophages are strongly represented in tumourmicroenvironment and are associated with a bad prognosis. Characterization of mechanismsleading to monocytes recruitment within the tumor is thus a major issue in anti-cancertherapeutic protocols optimization. Based on the differential expression of chemokinereceptors CCR2 and CX3CR1, two populations of monocytes, inflammatory monocytes(CCR2+, CX3CR1low) and resident monocytes (CCR2-, CX3CR1high) have been characterized inmice which are involved in monocytes recruitment and differentiation into macrophages.The main objective of my work was to better understand the mechanisms of monocytesmobilization following chemotherapeutic treatment. I started to study the role of chemokinereceptors with a focus on CX3CR1 in monocytes reconstitution following cyclophosphamide(CP) treatment. CP is an alkylant agent known for its myelosuppressive properties. Thischemotherapeutic agent induces a transitory anti tumour immune response associated witha monocyte renewal and a strong infiltration of the tumour by adoptively transferred Tlymphocytes. However, antigen-specific T cells are trapped by tumour-associated dendriticcells (TuDCs). This potentially decreases interactions between T lymphocytes and tumourcells suggesting an immunosuppressive role of TuDCs. CP induces a strong depletion ofmyeloid cells followed by a massive reconstitution of bone marrow and spleen monocytesreservoirs. CX3CR1 expression on bone marrow monocytes is decreased duringreconstitution and correlated with a decreasing adhesion of these cells to CX3CL1 ex vivo.We highlighted an increased mobilization of inflammatory monocytes in CX3CR1-/- micecompared to WT and CCR2-/-. Intra vital imaging of bone marrow within CX3CR1-/- mice orwith the help of a CX3CR1 antagonist allowed us to show a specific role of CX3CR1 in thelumen crawling and confinement of monocyte-derived cells in both sinusoid andparenchyma of the bone marrow. We suggest that CX3CR1 controls the release of bonemarrow monocytes during CP-induced mobilization. We think that modulating the rate ofcellular mobilization, by increasing the host’s leukocyte pool during CP inducedreconstitution and/or targeting CX3CR1, could contribute to improve cellular responsefollowing tissue damage or immune cell dysfunction. Furthermore, targeting CX3CR1couldprovide applications in the stem cell transplantation domain.
Role of chemokine receptor CX3CR1 in the monocytes mobilization induced by chemotherapy