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Published on: February 24, 2023
CD200 Blockade Modulates Tumor Immune Microenvironment but Fails to Show Efficacy in Inhibiting Tumor Growth in a
Fatemeh Talebian1, Jianyu Yu1, Kimberly Lynch1
1Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, United States.
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.
Insights
Blocking the CD200-CD200R pathway, a potential cancer immunotherapy, unexpectedly worsened melanoma growth in mice. This approach reduced anti-tumor T cell activity and showed no efficacy with checkpoint inhibitors, suggesting caution is needed.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- The CD200-CD200R pathway modulates immune responses and is implicated in various cancers.
- CD200 blockade is explored as an immunotherapy for CD200-positive cancers like melanoma.
- Understanding CD200 blockade effects in human-relevant models is crucial for therapeutic development.
Purpose of the Study:
- To evaluate the impact of CD200 blockade on melanoma growth and the tumor immune microenvironment (TIME).
- To investigate the efficacy of anti-CD200 therapy, alone or combined with checkpoint inhibitors, in a preclinical melanoma model.
Main Methods:
- Utilized the CD200-positive Yumm1.7 mouse melanoma model, bearing BRAF/PTEN mutations.
- Compared tumor growth and TIME in wild-type versus CD200R knockout mice.
- Assessed T cell function, gene expression (CCL8), and therapeutic efficacy of anti-CD200, anti-PD-1, and anti-CTLA4 antibodies.
Main Results:
- Yumm1.7 tumors grew significantly faster in CD200R knockout mice.
- CD200R deficiency or anti-CD200 treatment led to reduced immune cell infiltration, impaired T cell effector functions (IFN-γ+, TNF-α+), and decreased TCR clonality in tumors.
- CCL8 gene was upregulated in CD200R-deficient tumors and macrophages.
- Anti-CD200 therapy, alone or with checkpoint inhibitors, failed to inhibit tumor growth.
Conclusions:
- CD200 blockade in this model resulted in suppressed anti-tumor T cell responses within the tumor microenvironment.
- The findings suggest that CD200 blockade may not be an effective immunotherapy for melanoma and should be approached with caution.
- Further research is needed to elucidate the complex role of the CD200-CD200R pathway in cancer immunity.
