Cancer-derived sialylated IgG promotes tumor immune escape by binding to Siglecs on effector T cells

Zihan Wang; Zihan Geng; Wenwei Shao; Enyang Liu; Jingxuan Zhang; Jingshu Tang; Pingzhang Wang; Xiuyuan Sun; Lin Xiao; Weiyan Xu; Youhui Zhang; Heng Cui; Liang Zhang; Xi Yang; Xiaohong Chang; Xiaoyan Qiu

doi:10.1038/s41423-019-0327-9

Cancer-derived sialylated IgG promotes tumor immune escape by binding to Siglecs on effector T cells

Cell Mol Immunol. 2020 Nov;17(11):1148-1162. doi: 10.1038/s41423-019-0327-9. Epub 2019 Nov 21.

Authors

Zihan Wang^#^{1

2

3}, Zihan Geng^#^{1

2

3}, Wenwei Shao^{1

2}, Enyang Liu^{1

2}, Jingxuan Zhang^{1

2}, Jingshu Tang^{1

2}, Pingzhang Wang^{1

3}, Xiuyuan Sun^{1

2}, Lin Xiao⁴, Weiyan Xu^{1

2}, Youhui Zhang⁵, Heng Cui⁶, Liang Zhang⁷, Xi Yang⁷, Xiaohong Chang⁸, Xiaoyan Qiu^{9

10

11}

Affiliations

¹ Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
² NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China.
³ Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, 100191, China.
⁴ Department of Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
⁵ Department of Immunology, Cancer Institute & Hospital, Chinese Academy of Medical Science, Beijing, 100021, China.
⁶ Gynecologic Oncology Center of Peking University Peoples' Hospital, Beijing, 100044, China.
⁷ Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, Guangdong, 518057, China.
⁸ Gynecologic Oncology Center of Peking University Peoples' Hospital, Beijing, 100044, China. changxiaohong@pkuph.edu.cn.
⁹ Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. qiuxy@bjmu.edu.cn.
¹⁰ NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China. qiuxy@bjmu.edu.cn.
¹¹ Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, 100191, China. qiuxy@bjmu.edu.cn.

^# Contributed equally.

Abstract

To date, IgG in the tumor microenvironment (TME) has been considered a product of B cells and serves as an antitumor antibody. However, in this study, using a monoclonal antibody against cancer-derived IgG (Cancer-IgG), we found that cancer cells could secrete IgG into the TME. Furthermore, Cancer-IgG, which carries an abnormal sialic acid modification in the CH1 domain, directly inhibited effector T-cell proliferation and significantly promoted tumor growth by reducing CD4⁺ and CD8⁺ T-cell infiltration into tumor tissues. Mechanistic studies showed that the immunosuppressive effect of sialylated Cancer-IgG is dependent on its sialylation and binding to sialic acid-binding immunoglobulin-type lectins (Siglecs) on effector CD4⁺ and CD8⁺ T cells. Importantly, we show that several Siglecs are overexpressed on effector T cells from cancer patients, but not those from healthy donors. These findings suggest that sialylated Cancer-IgG may be a ligand for Siglecs, which may serve as potential checkpoint proteins and mediate tumor immune evasion.

Keywords: Cancer-derived IgG; IgG; sialylation; tumor immune escape; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / cytology
CD8-Positive T-Lymphocytes / immunology
Cell Line, Tumor
Cell Proliferation
Female
Humans
Immunoglobulin Fab Fragments / metabolism
Immunoglobulin G / chemistry
Immunoglobulin G / metabolism*
Lymphocyte Count
Mice
N-Acetylneuraminic Acid / metabolism*
Neoplasms / immunology*
Neoplasms / metabolism*
Protein Binding
Protein Domains
Sialic Acid Binding Immunoglobulin-like Lectins / metabolism*
T-Lymphocytes / cytology
T-Lymphocytes / immunology*
Tissue Donors
Tumor Escape*
Tumor Microenvironment / immunology

Substances

Immunoglobulin Fab Fragments
Immunoglobulin G
Sialic Acid Binding Immunoglobulin-like Lectins
N-Acetylneuraminic Acid