Abstract 5831: CD200R signaling contributes to unfavorable tumor microenvironment through regulating production of chemokines by tumor associated macrophages

Abstract

Abstract CD200 is overexpressed in human solid tumors such as neuroblastoma and melanoma and is considered as an immune checkpoint molecule for dampening cancer immunity. However, how CD200 affects tumor microenvironment (TME) and host immunity is incompletely understood. In the present study, we evaluated the role of the CD200-CD200R pathway in TME using loss-of-function CD200R-/- mice, along with two clinically relevant, CD200-positive murine tumor models: the mouse neuroblastoma NB9464D and melanoma Yummer1.7. We found that comparing with the wild type mice, CD200R-/- mice were significantly more potent in rejecting these CD200+ tumors. Transcriptome analysis by single cell RNA sequencing demonstrated that tumors from CD200R-/- mice had more infiltration of CD45+ immune cells, including CD4+ and CD8+ T cells, and NK cells but less infiltration of neutrophils. Antibody depletion experiments revealed that immune effectors including CD8+ T cells and NK cells in combination, are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling differentially regulates the expression of chemokines in tumor-associated macrophages (TAMs). In the absence of CD200R, TAMs up-regulate CCL24 and CCL8 and down-regulate CXCL3, CXCL2, and CCL3 via activation of ERK and/or p38 MAP kinases. Increased expression of CCL24 in CD200R-deficient tumors resulted in increased infiltration of eosinophils, which also contributes to anti-tumor activity. Overall, we conclude that CD200R-mediated signaling, via interaction with CD200 on tumor cells, contributes to unfavorable TME primarily through chemokine-dependent recruitment of immune suppressive neutrophils and exclusion of anti-cancer immune effectors. Our study has significant implications in developing CD200-targeted immunotherapy of solid tumors. Citation Format: Cho-Hao Lin, Fatemeh Talebian, Yang Li, Jianmin Zhu, Bolin Zhao, Jin-Qing Liu, Sujit Basu, Xueling Pan, Xi Chen, Pearlly Yan, William E. Carson, Gang Xin, Haitao Wen, Ruoning Wang, Zihai Li, Qin Ma, Xue-Feng Bai. CD200R signaling contributes to unfavorable tumor microenvironment through regulating production of chemokines by tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5831.