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bioRxiv · 10.1101/2022.07.08.499173

Glioma-derived CCL2 and CCL7 mediate migration of immune suppressive CCR2+ myeloid cells into the tumor microenvironment in a redundant manner

Takacs, G. P.·Kreiger, C. J.·Luo, D.·Tian, G.·Garcia, J. S.·Deleyrolle, L. P.·Mitchell, D. A.·Harrison, J. K.
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Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized in part by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive, hematopoietic cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a potent subset of myeloid cells, expressing monocytic (M)-MDSC markers, distinguished by dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate into the TME. This study evaluated the T cell suppressive function and migratory properties of CCR2+/CX3CR1+ MDSCs. Bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Recombinant and glioma-derived CCL2 and CCL7 induce the migration of CCR2+/CX3CR1+ MDSCs with similar efficacy. KR158B-CCL2 and -CCL7 knockdown murine gliomas contain equivalent percentages of CCR2+/CX3CR1+ MDSCs compared to KR158B gliomas. Combined neutralization of CCL2 and CCL7 completely blocks CCR2-expressing cell migration to KR158B cell conditioned media. High levels of CCL2 and CCL7 are also associated with negative prognostic outcomes in GBM patients. These data provide a more comprehensive understanding of the function of CCR2+/CX3CR1+ MDSCs and the role of CCL2 and CCL7 in the recruitment of these immune suppressive cells and further support the significance of targeting this chemokine axis in GBM.

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Takacs, G. P., Kreiger, C. J., Luo, D., Tian, G., Garcia, J. S., Deleyrolle, L. P., Mitchell, D. A., Harrison, J. K.. 2022-07-08. Glioma-derived CCL2 and CCL7 mediate migration of immune suppressive CCR2+ myeloid cells into the tumor microenvironment in a redundant manner. https://doi.org/10.1101/2022.07.08.499173

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