CX(3)CR1 Delineates Temporally and Functionally Distinct Subsets of Myeloid-Derived Suppressor Cells in a Mouse Model of Ovarian Cancer

Expression of the chemokine receptor CX(3)CR1 has been used to identify distinct populations within the monocyte, macrophage and dendritic cell lineages. Recent evidence indicates that CX(3)CR1-positive subsets of myeloid cells play distinct and important roles in a wide range of immunological maladies and thus the use of CX(3)CR1 expression has leveraged our understanding of the myeloid contribution to a multitude of diseases. Here we use CX(3)CR1 expression as a means to identify a novel non-granulocytic CX(3)CR1-negative myeloid population that is functionally distinct from the previously-described CX(3)CR1-positive cellular subsets within the CD11b-positive cellular compartment of ascites from ovarian tumor-bearing mice. We functionally identify CX(3)CR1-negative cells as myeloid suppressor cells and as a cellular subset with pathological specificity. Importantly, the CX(3)CR1-negative cells exhibit early IL-10 production in the ovarian tumor microenvironment, which we have shown to be critically tied to suppression and further MDSC accumulation, and we now show that this cellular population actively contributes to tumor progression. Furthermore, we demonstrate that the CX(3)CR1-negative population is derived from the recently described CX(3)CR1-positive macrophage/dendritic cell precursor (MDP) cell. These studies provide a greater understanding of the generation and maintenance of regulatory myeloid subsets and have broad implications for the elucidation of myeloid function and contributions within the tumor microenvironment.