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CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment
Chao Xin1, Jianmin Zhu1, Song Gu2
1Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Patients with pediatric cancers such as neuroblastoma (NB) are often unresponsive to checkpoint blockade immunotherapy. One major factor in pediatric tumor resistance to immunotherapy is considered to be the low mutation rate of pediatric tumors. Another factor may be the overexpression of additional inhibitory pathways. While analyzing the RNA-sequencing database TARGET, we found that human NB tumors overexpress immune checkpoint molecule CD200. To determine its significance and impact on tumor immune microenvironment, we analyzed 49 cases of previously untreated, surgically removed NB tumors using immunohistochemistry and multi-color flow cytometry (FACS). We found that CD200 is overexpressed in more than 90% of NB tumors. In the tumor microenvironment of NB, CD200 is mainly overexpressed in CD45- NB tumor cells, while its cognate receptor (CD200R) is mainly expressed in HLA-DR+CD14+ myeloid cells and CD11c+ dendritic cells. Low-level expression of CD200R is also observed in tumor-infiltrating CD4+ and CD8+ T cells. In NB tumors with higher CD200 expression (CD200high), we observed lower numbers of HLA-DR+CD14+ myeloid cells and less tumor-infiltrating CD4+ and CD8+ T cells. Moreover, we found that CD4+ and CD8+ T cells produced less IFN-γ and/or TNF-α in CD200high NB tumors. Thus, CD200-CD200R pathway appears to downregulate anti-tumor immunity in the tumor microenvironment of NB tumors, and blockade of this pathway may be beneficial for NB patients.
Insights
Neuroblastoma (NB) tumors often resist immunotherapy due to low mutation rates and immune evasion. This study reveals CD200 overexpression in NB, which suppresses anti-tumor immunity by reducing immune cell infiltration and function.
Area of Science:
- Immunology
- Oncology
- Pediatric Cancer Research
Background:
- Pediatric cancers, including neuroblastoma (NB), exhibit resistance to checkpoint blockade immunotherapy.
- Tumor mutation burden and additional inhibitory pathways contribute to this resistance.
- Overexpression of immune checkpoint molecule CD200 was identified in NB tumors via the TARGET database.
Purpose of the Study:
- To investigate the significance and impact of CD200 overexpression on the tumor immune microenvironment in neuroblastoma.
- To determine the expression patterns of CD200 and its receptor (CD200R) in NB tumors.
- To correlate CD200 expression levels with immune cell infiltration and function.
Main Methods:
- Analysis of 49 untreated, surgically removed NB tumors.
- Immunohistochemistry and multi-color flow cytometry (FACS) for protein expression analysis.
- Quantification of immune cell populations and cytokine production (IFN-γ, TNF-α).
Main Results:
- CD200 was overexpressed in over 90% of NB tumors, primarily on NB cells.
- CD200 receptor (CD200R) was mainly expressed on myeloid cells and dendritic cells, with low expression on T cells.
- CD200-high NB tumors showed reduced infiltration of myeloid cells, dendritic cells, CD4+, and CD8+ T cells.
- T cells in CD200-high tumors exhibited decreased production of IFN-γ and TNF-α.
Conclusions:
- The CD200-CD200R pathway suppresses anti-tumor immunity within the NB tumor microenvironment.
- Targeting the CD200-CD200R pathway represents a potential therapeutic strategy for neuroblastoma patients.
- Further research into CD200 pathway blockade may enhance immunotherapy efficacy in pediatric cancers.
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