CX3CR1 delineates temporally and functionally distinct subsets of myeloid-derived suppressor cells in a mouse model of ovarian cancer.

ABSTRACT

Expression of the chemokine receptor CX3CR1 has been used to identify distinct populations within the monocyte, macrophage and dendritic cell lineages. Recent evidence indicates that CX3CR1-positive subsets of myeloid cells play distinct and important roles in a wide range of immunological maladies, and thus the use of CX3CR1 expression has leveraged our understanding of the myeloid contribution to a multitude of diseases. Here we use CX3CR1 expression as a means to identify a novel nongranulocytic CX3CR1-negative myeloid population that is functionally distinct from the previously described CX3CR1-positive cellular subsets within the CD11b-positive cellular compartment of ascites from ovarian tumor-bearing mice. We functionally identify CX3CR1-negative cells as myeloid suppressor cells and as a cellular subset with pathological specificity. Importantly, the CX3CR1-negative cells exhibit early IL-10 production in the ovarian tumor microenvironment, which we have shown to be critically tied to suppression and additional myeloid-derived suppressor cell accumulation, and we now show that this cellular population actively contributes to tumor progression. Furthermore, we demonstrate that the CX3CR1-negative population is derived from the recently described CX3CR1-positive macrophage/dendritic cell precursor 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.