本期文章：《免疫》：Online/在线发表

中山大学邝栋明等研究人员合作发现，免疫检查点疗法引发的IgG抗体唾液酸化损害肝细胞癌的抗肿瘤I型干扰素反应。2022年12月22日，《免疫》杂志在线发表了该论文。

利用串联质谱分析来自肝癌组织的免疫球蛋白G（IgG）的修饰，研究人员确定了免疫检查点阻断（ICB）疗法在催化Fc区IgG唾液酸化中的作用。效应T细胞通过干扰素（IFN）-γ-ST6Gal-I依赖性的途径触发了IgG的唾液酸化。DC-SIGN⁺巨噬细胞代表了唾液酸化IgG的主要靶标细胞。

在与唾液酸化的IgG相互作用时，DC-SIGN刺激Raf-1激发的ATF3升高，从而使cGAS-STING途径失活，并消除了随后I型IFN触发的抗肿瘤免疫。尽管肿瘤中IgG唾液酸化的增强预示着接受ICB治疗的患者的治疗效果会得到改善，但阻碍IgG唾液酸化会增强ICB治疗后的抗肿瘤性T细胞免疫力。因此，针对ICB治疗中基于抗体的负反馈作用，有可能提高癌症免疫疗法的疗效。

据介绍，响应ICB疗法而重新激活抗肿瘤T细胞的做法已得到证实。然而，ICB疗法是否以及如何操纵癌症环境中的抗体介导的免疫反应，仍然是一个未知数。

附：英文原文

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

Author: 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

Issue&Volume: 2022-12-22

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-mediatedimmune response in cancer environments, however, remains elusive. Using tandem massspectrometric 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-dependentpathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interactingwith sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivatedcGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenicimmunity. Although enhanced IgG sialylation in tumors predicted improved therapeuticoutcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenicT cell immunity after ICB therapy. Thus, targeting antibody-based negative feedbackaction of ICB therapy has potential for improving efficacy of cancer immunotherapies.

DOI: 10.1016/j.immuni.2022.11.014