CD200R signaling regulates myeloid cell production of chemokines in tumor microenvironment
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ABSTRACT:
PROVIDER: PRJNA873063 | ENA |
REPOSITORIES: ENA
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Project description:CD200 is overexpressed in human solid tumors such as neuroblastoma and melanoma and considered to be a checkpoint molecule to be targeted for cancer immunotherapy. However, its role in tumor microenvironment (TME) is not well understood. In this study, we evaluated the role of CD200-CD200R pathway in TME using two human relevant, CD200-positive murine tumor models, i.e. the mouse neuroblastoma NB9464D, and melanoma Yummer1.7 models. We found that in CD200R-/- mice, both tumor types grew significantly slower than in wild type mice. TME analyses using scRNAseq and flow cytometry revealed that tumors from CD200R-/- mice overall recruited more CD45+ immune cells including CD4+ and CD8+ T cells and NK cells but less neutrophils into tumors. Antibody depletion experiments revealed that immune effectors including CD4+ and CD8+ T cells, and NK cells are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling differentially regulates the expression of chemokines in TAMs. In the absence of CD200R, TAMs upregulate CCL24 and CCL8 and downregulate CXCL3, CXCL2 and CCL3 via activation of Erk and/or P38 MAP kinases. Increased expression of CCL24 in TAMs resulted in increased recruitment of eosinophils, which contributes to anti-tumor activity. Thus, CD200R signaling regulates myeloid cell production of chemokines in TME, which explains the differential recruitment of immune effectors and downregulation of neutrophils.
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Project description:CD200 is overexpressed in many solid tumors and considered as an immune checkpoint molecule dampening cancer immunity. In this study, we found that CD200R-/- mice were significantly more potent in rejecting these CD200+ tumors. scRNA sequencing demonstrated that tumors from CD200R-/- mice had more infiltration of CD4+ and CD8+ T cells, and NK cells but less infiltration of neutrophils. Antibody depletion experiments revealed that immune effector cells are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling regulates the expression of chemokines in tumor-associated myeloid cells (TAMCs). In the absence of CD200R, TAMCs increased expression of CCL24 and resulted in increased infiltration of eosinophils, which contributes to anti-tumor activity. Overall, we conclude that CD200R signaling contributes to unfavorable TME through chemokine-dependent recruitment of immune suppressive neutrophils and exclusion of anti-cancer immune effectors. Our study has implications in developing CD200-CD200R targeted immunotherapy of solid tumors.
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