抑制检查点SIRPα的顺式相互作用阻碍了抗癌免疫反应

IF 16.3 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-10-10 DOI:10.1126/sciimmunol.adv5085

Zhenghai Tang, Ming-Chao Zhong, Jin Qian, Jiayu Dou, Lok San Wong, Jiaxin Li, Cristian Camilo Galindo, Dominique Davidson, André Veillette

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引用次数: 0

摘要

信号调节蛋白α (SIRPα)是一种巨噬细胞抑制受体，通过与肿瘤细胞上的CD47反式相互作用来限制吞噬和抗肿瘤活性。在这里，我们发现SIRPα抑制功能的一个组成部分独立于CD47发生。抑制的发生是由于巨噬细胞表面顺式中SIRPα和CD18 （β 2整合素）的相互作用，涉及的SIRPα氨基酸与SIRPα- cd47相互作用中涉及的氨基酸不同。这种顺式相互作用阻止了CD18的激活，而CD18是吞噬所必需的。SIRPα-CD18和SIRPα-CD47的联合阻断是在体内最大化吞噬和抑制肿瘤生长所必需的。因此，抑制免疫检查点（如SIRPα）通过顺式靶向CD18的机制抑制细胞活化，该机制除了与反式中的抑制检查点配体结合外，还会发生。在开发用于免疫治疗的抑制性检查点阻断时，应考虑这种双重作用模式。

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Anticancer immune responses are hindered by cis interaction of inhibitory checkpoint SIRPα

Signal regulatory protein α (SIRPα) is a macrophage inhibitory receptor that limits phagocytosis and antitumor activity by interacting in trans with CD47 on tumor cells. Here, we found that a component of SIRPα’s inhibitory function occurred independently of CD47. Inhibition occurred because of interactions between SIRPα and CD18 (β₂ integrin) in cis on the surface of macrophages, involving SIRPα amino acids distinct from those implicated in the SIRPα-CD47 interaction. This cis interaction prevented activation of CD18, which is necessary for phagocytosis. The combined blockade of SIRPα-CD18 and SIRPα-CD47 was essential for maximizing phagocytosis and suppression of tumor growth in vivo. Thus, inhibitory immune checkpoints such as SIRPα suppress cell activation through a mechanism targeting CD18 in cis, which occurs in addition to engagement by their inhibitory checkpoint ligands in trans. This dual mode of action should be considered when developing inhibitory checkpoint blockades for immunotherapy.

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.