AUTHOR=Talebian Fatemeh , Yu Jianyu , Lynch Kimberly , Liu Jin-Qing , Carson William E. , Bai Xue-Feng TITLE=CD200 Blockade Modulates Tumor Immune Microenvironment but Fails to Show Efficacy in Inhibiting Tumor Growth in a Murine Model of Melanoma JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=9 YEAR=2021 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.739816 DOI=10.3389/fcell.2021.739816 ISSN=2296-634X ABSTRACT=

CD200-CD200R pathway regulates immune responses and has been implicated in the pathogenesis of a number of cancer types. CD200 blockade is considered a strategy for immunotherapy of CD200-positive cancers such as melanoma. Thus, it is critical to understand the potential impacts of CD200 blockade in a more human relevant tumor model. In this study, we evaluated these issues using the CD200+ Yumm1.7 mouse melanoma model. Yumm1.7 cells bear Braf/Pten mutations resembling human melanoma. We found that Yumm1.7 tumors grow significantly faster in CD200R–/– mice compared to wild type mice. Analysis of tumor immune microenvironment (TIME) revealed that tumors from CD200R–/– or anti-CD200 treated mice had downregulated immune cell contents and reduced TCR clonality compared to tumors from untreated wild type mice. T cells also showed impaired effector functions, as reflected by reduced numbers of IFN-γ+ and TNF-α+ T cells. Mechanistically, we found upregulation of the CCL8 gene in CD200R–/– tumors. In vitro co-culture experiments using Yumm1.7 tumor cells with bone marrow derived macrophages (BMDM) from WT and CD200R–/– mice confirmed upregulation of macrophage CCL8 in the absence of CD200-CD200R interaction. Finally, we found that anti-CD200 therapy failed to show efficacy either alone or in combination with checkpoint inhibitors such as anti-PD-1 or anti-CTLA4 in inhibiting Yumm1.7 tumor growth. Given that CD200R-deficiency or anti-CD200 treatment leads to reduced T cell responses in TME, using blockade of CD200 as an immunotherapy for cancers such as melanoma should be practiced with caution.