CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment
CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment
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CD200在神经母细胞瘤中过度表达并调节肿瘤免疫微环境
DOI：
10.1007/s00262-020-02589-6
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发表时间：
2020-06-08
影响因子：
5.8
通讯作者：
Zhu, Hua
中科院分区：
文献类型：
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作者：
Xin, Chao;Zhu, Jianmin;Zhu, Hua
小儿癌症患者如神经母细胞瘤（NB）通常对检查点阻断免疫治疗无反应。儿童肿瘤对免疫治疗产生耐药性的一个主要因素被认为是儿童肿瘤的低突变率。另一个因素可能是额外抑制途径的过度表达。通过分析rna测序数据库TARGET，我们发现人NB肿瘤过表达免疫检查点分子CD200。为了确定其对肿瘤免疫微环境的意义和影响，我们使用免疫组织化学和多色流式细胞术（FACS）分析了49例未经治疗的手术切除的NB肿瘤。我们发现CD200在超过90%的NB肿瘤中过表达。在NB的肿瘤微环境中，CD200主要在CD45(-)NB肿瘤细胞中过表达，而其同源受体CD200R主要在HLA-DR(+)CD14（+）骨髓细胞和CD11c（+）树突状细胞中表达。在肿瘤浸润的CD4（+）和CD8(+)T细胞中也观察到低水平表达CD200R。在CD200高表达（CD200（高））的NB肿瘤中，我们观察到HLA-DR(+)CD14（+）骨髓细胞数量减少，肿瘤浸润的CD4（+）和CD8(+)T细胞数量减少。此外，我们发现CD4（+）和CD8(+)T细胞在CD200（高）NB肿瘤中产生较少的ifn - γ和/或tnf - α。因此，CD200-CD200R通路似乎下调了NB肿瘤微环境中的抗肿瘤免疫，阻断该通路可能对NB患者有益。
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 (CD200(high)), 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-gamma and/or TNF-alpha in CD200(high)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.