Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma.

Abstract

The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.

• Authors: Rui-Qi Wu, Xiang-Ming Lao, Dong-Ping Chen, Hongqiang Qin, Ming Mu, Wen-Jie Cao, Jia Deng, Chao-Chao Wan, Wan-Yu Zhan, Jun-Cheng Wang, Li Xu, Min-Shan Chen, Qiang Gao, Limin Zheng, Yuan Wei, Dong-Ming Kuang
• Journal: Immunity (Immunity) Vol. 56 Issue 1 Pg. 180-192.e11 (01 10 2023) ISSN: 1097-4180 [Electronic] United States
• PMID: 36563676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Immunoglobulin G
• Interferon Type I

Topics

• Humans
• Immunoglobulin G
• Carcinoma, Hepatocellular (drug therapy)
• Interferon Type I
• Liver Neoplasms (drug therapy)
• Immunotherapy (methods)