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CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment

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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.

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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

HB:

Hepatoblastoma

IgSF:

Immunoglobulin superfamily

IHC:

Immunohistochemistry

INSS:

International Neuroblastoma Staging System

MDSC:

Myeloid-derived suppressor cell

MFI:

Mean fluorescence intensity

NB:

Neuroblastoma

pDC:

Plasmacytoid dendritic cell

RS:

Rhabdomyosarcoma

TADC:

Tumor-associated dendritic cell

TAM:

Tumor-associated macrophage

TAMC:

Tumor-associated myeloid cell

TARGET:

Therapeutically Applicable Research to Generate Effective Treatments

TIL:

Tumor-infiltrating lymphocyte

TME:

Tumor microenvironment

Treg:

Regulatory T cell

WT:

Wilms tumor

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Acknowledgements

This study was supported by the grants from the National Natural Science Foundation of China (Grant Nos. 81800118, 81773039) and Project of Shanghai Science and Technology Committee (Grant Nos. 17441903200, 17411950402).

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Authors and Affiliations

  1. Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Chao Xin, Jianmin Zhu, Xi Mo & Hua Zhu

  2. Department of Hematology and Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dong Fang Road, Pu Dong New District, Shanghai, 200127, China

    Ci Pan, Jingyan Tang & Hua Zhu

  3. Department of General Surgery/Surgical Oncology Center, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dong Fang Road, Pu Dong New District, Shanghai, 200017, China

    Song Gu & Min Xu

  4. Department of Pathology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Minzhi Yin & Jing Ma

  5. Division of Immunotherapy, Institute of Human Virology, University of Maryland, School of Medicine, Baltimore, MD, 21201, USA

    Peng Zhang & Yang Liu

  6. Department of Pathology, College of Medicine and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    Xue-Feng Bai

Authors
  1. Chao Xin
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  2. Jianmin Zhu
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  3. Song Gu
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  4. Minzhi Yin
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  9. Yang Liu
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  10. Xue-Feng Bai
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  11. Xi Mo
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  12. Min Xu
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  13. Hua Zhu
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Contributions

XB conceived and designed the experiments. CX and HZ performed the experiments and analyzed the data. XB, HZ and CX wrote the manuscript. JZ arranged the panels for flow cytometry. MX and SG prepared the patient samples. MY and JM diagnosed and provided patients’ information. YL and PZ helped to obtain and analyze RNA-seq data. XM, JT and CP provided assistance with revising the manuscript. All authors read and approved the manuscript.

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Correspondence to Min Xu or Hua Zhu.

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Xin, C., Zhu, J., Gu, S. et al. CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment. Cancer Immunol Immunother 69, 2333–2343 (2020). https://doi.org/10.1007/s00262-020-02589-6

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