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Immune checkpoint markers and anti-CD20-mediated NK cell activation
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2020-12-08 , DOI: 10.1002/jlb.5a0620-365r
Zhaoming Wang 1, 2 , George J Weiner 1, 2, 3
Affiliation  

Anti-CD20 mAb is an effective therapy for most B-cell malignancies. Checkpoint blockade has been used to enhance T-cell-mediated antitumor response. Little is known about the biologic significance of immune checkpoints expressed by NK cells in anti-CD20-based therapy. To investigate the role of checkpoints in anti-CD20-mediated NK cell biology, Raji B-cell lymphoma cells, and PBMCs from normal donors were cocultured with rituximab (RTX), obinutuzumab (OBZ), or trastuzumab as a control mAb for between 20 h and 9 d. RTX and OBZ induced a dose-dependent NK cell up-regulation of T-cell immunoreceptor with Ig and ITIM domain (TIGIT) and T-cell immunoglobulin mucin-3 (TIM3), but not PD1, CTLA4, or LAG3. Resting CD56dim NK had higher TIGIT and TIM3 expression than resting CD56bright NK although TIGIT and TIM3 were up-regulated on both subsets. NK cells with the CD16 158VV single nucleotide polymorphism had greater TIM3 up-regulation than did NK from VF or FF donors. TIGIT+ and TIM3+ NK cells degranulated, produced cytokines, and expressed activation markers to a greater degree than did TIGIT or TIM3 NK cells. Blockade of TIGIT, TIM3, or both had little impact on RTX-induced NK cell proliferation, degranulation, cytokine production, or activation. Taken together, TIGIT and TIM3 can serve as markers for anti-CD20-mediated NK cell activation, but may not serve well as targets for enhancing the anti-tumor activity of such therapy.

中文翻译:

免疫检查点标志物和抗 CD20 介导的 NK 细胞活化

抗 CD20 mAb 是大多数 B 细胞恶性肿瘤的有效疗法。检查点阻断已被用于增强 T 细胞介导的抗肿瘤反应。关于 NK 细胞表达的免疫检查点在基于抗 CD20 的治疗中的生物学意义知之甚少。为了研究检查点在抗 CD20 介导的 NK 细胞生物学中的作用,将来自正常供体的 Raji B 细胞淋巴瘤细胞和 PBMC 与利妥昔单抗 (RTX)、obinutuzumab (OBZ) 或曲妥珠单抗作为对照 mAb 共培养 20 h 和 9 d。RTX 和 OBZ 诱导具有 Ig 和 ITIM 结构域 (TIGIT) 和 T 细胞免疫球蛋白粘蛋白 3 (TIM3) 的 T 细胞免疫受体的剂量依赖性 NK 细胞上调,但不是 PD1、CTLA4 或 LAG3。静息 CD56 dim NK 的 TIGIT 和TIM3表达高于静息 CD56 BrightNK 尽管 TIGIT 和 TIM3 在两个亚群上均上调。具有 CD16 158VV 单核苷酸多态性的 NK 细胞比来自 VF 或 FF 供体的 NK 具有更大的 TIM3 上调。与 TIGIT –或 TIM3 NK 细胞相比, TIGIT +和 TIM3 + NK 细胞脱粒、产生细胞因子和表达激活标志物的程度更高。TIGIT、TIM3 或两者的阻断对 RTX 诱导的 NK 细胞增殖、脱粒、细胞因子产生或激活几乎没有影响。总之,TIGIT 和 TIM3 可以作为抗 CD20 介导的 NK 细胞活化的标志物,但可能不能很好地作为增强这种疗法的抗肿瘤活性的靶标。
更新日期:2020-12-08
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