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

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

  • Immunity. 2022 Dec 13;S1074-7613(22)00604-5. doi: 10.1016/j.immuni.2022.11.014.
Rui-Qi Wu 1 Xiang-Ming Lao 1 Dong-Ping Chen 1 Hongqiang Qin 2 Ming Mu 1 Wen-Jie Cao 1 Jia Deng 1 Chao-Chao Wan 1 Wan-Yu Zhan 1 Jun-Cheng Wang 1 Li Xu 1 Min-Shan Chen 1 Qiang Gao 3 Limin Zheng 1 Yuan Wei 4 Dong-Ming Kuang 5
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China.
  • 2 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
  • 3 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China. Electronic address: [email protected]
  • 5 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China. Electronic address: [email protected]
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.

Keywords

DC-SIGN(+) macrophages; immunotherapy; sialylated IgG; type I interferon response.

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