CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment
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ORIGINAL ARTICLE
CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment Chao Xin1 · Jianmin Zhu1 · Song Gu3 · Minzhi Yin4 · Jing Ma4 · Ci Pan2 · Jingyan Tang2 · Peng Zhang5 · Yang Liu5 · Xue‑Feng Bai6 · Xi Mo1 · Min Xu3 · Hua Zhu1,2 Received: 5 December 2019 / Accepted: 23 April 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords CD200 · CD200R · Neuroblastoma · Tumor immune microenvironment · Tumor-infiltrating lymphocyte Abbreviations ACC Adrenocortical carcinoma AML Acute myeloid leukemia ATCC American Type Culture Collection BSA Bovine serum albumin CD200R CD200 receptor
CLL Chronic lymphocytic leukemia DC Dendritic cell EMEM Eagle’s Minimum Essential Medium FBS Fetal bovine serum FPKM Fragments Per Kilobase of transcript per Million fragments mapped
* Min Xu [email protected]
4
Department of Pathology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
5
Division of Immunotherapy, Institute of Human Virology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
6
Department of Pathology, College of Medicine and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
* Hua Zhu zhu‑[email protected] 1
Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2
Department of Hematology and Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 D
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