CD47-SIRPα Controls ADCC Killing of Primary T Cells by PMN Through a Combination of Trogocytosis and NADPH Oxidase Activation.
CD47-SIRPα Controls ADCC Killing of Primary T Cells by PMN Through a Combination of Trogocytosis and NADPH Oxidase Activation.
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DOI：
10.3389/fimmu.2022.899068
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发表时间：
2022
影响因子：
7.3
通讯作者：
Olive, Daniel
中科院分区：
文献类型：
--
作者：
Gondois-Rey, Francoise;Miller, Thomas;Laletin, Vladimir;Morelli, Xavier;Collette, Yves;Nunes, Jacques;Olive, Daniel
关键词：
靶向由CD47 SIRPα相互作用构成的“不要吃我”骨髓检查点的免疫疗法具有很好的临床潜力，但受非肿瘤细胞破坏相关毒性的限制。这些剂量限制性毒性表明，需要强调抗cd47 - sirp α治疗对非肿瘤携带cd47细胞的作用机制。考虑到接受抗cd47抗体的患者淋巴细胞减少的发生率增加以及多形核细胞（PMNs）的强ADCC（抗体依赖性细胞毒性）效应功能，我们研究了在抗cd47单克隆抗体存在下，原代PMNs与原代T细胞共培养的行为。PMN以cd47 - mab依赖的方式杀死T细胞，PMN与T细胞的比例为1:1。观察到的细胞毒性是由经典ADCC和CD47-SIRPα检查点阻断诱导的细胞吞噬和强烈的呼吸爆发的新组合产生的。CD47阻断单抗的复杂作用可以通过结合其单个机制元件：ADCC， SIRPα阻断和ROS诱导来概括。尽管之前的研究已经得出结论，PMNs中SIRPα信号的破坏仅限于trogocytoosis特异性细胞毒性，但我们的研究结果表明，SIRPα也严格控制NADPH氧化酶的激活，这一功能在未成熟PMNs的分化过程中得到证实，但在成熟PMNs中尚未得到证实。总之，我们的研究结果强调需要将pmn整合到靶向CD47-SIRPα免疫检查点的分子开发中，并设计能够增强髓细胞功能的药物，同时限制对能够参与抗肿瘤免疫应答的健康细胞的不良影响。
Immunotherapies targeting the “don’t eat me” myeloid checkpoint constituted by CD47 SIRPα interaction have promising clinical potential but are limited by toxicities associated with the destruction of non-tumor cells. These dose-limiting toxicities demonstrate the need to highlight the mechanisms of anti–CD47-SIRPα therapy effects on non-tumor CD47-bearing cells. Given the increased incidence of lymphopenia in patients receiving anti-CD47 antibodies and the strong ADCC (antibody-dependent cellular cytotoxicity) effector function of polymorphonuclear cells (PMNs), we investigated the behavior of primary PMNs cocultured with primary T cells in the presence of anti-CD47 mAbs. PMNs killed T cells in a CD47-mAb–dependent manner and at a remarkably potent PMN to T cell ratio of 1:1. The observed cytotoxicity was produced by a novel combination of both trogocytosis and a strong respiratory burst induced by classical ADCC and CD47-SIRPα checkpoint blockade. The complex effect of the CD47 blocking mAb could be recapitulated by combining its individual mechanistic elements: ADCC, SIRPα blockade, and ROS induction. Although previous studies had concluded that disruption of SIRPα signaling in PMNs was limited to trogocytosis-specific cytotoxicity, our results suggest that SIRPα also tightly controls activation of NADPH oxidase, a function demonstrated during differentiation of immature PMNs but not so far in mature PMNs. Together, our results highlight the need to integrate PMNs in the development of molecules targeting the CD47-SIRPα immune checkpoint and to design agents able to enhance myeloid cell function while limiting adverse effects on healthy cells able to participate in the anti-tumor immune response.
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影响因子：
11.2
作者：
Chao MP;Alizadeh AA;Tang C;Jan M;Weissman-Tsukamoto R;Zhao F;Park CY;Weissman IL;Majeti R
通讯作者：
Majeti R
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
CD47是人类急性髓样白血病干细胞的不良预后因素和治疗抗体靶标。
影响因子：
64.5
作者：
Majeti R;Chao MP;Alizadeh AA;Pang WW;Jaiswal S;Gibbs KD Jr;van Rooijen N;Weissman IL
通讯作者：
Weissman IL
DOI：
10.1083/jcb.135.2.533
发表时间：
1996-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gao AG;Lindberg FP;Dimitry JM;Brown EJ;Frazier WA
通讯作者：
Frazier WA
影响因子：
4.8
作者：
Frazier, WA;Gao, AG;Linder, ME
通讯作者：
Linder, ME