Cancer Biology Graduate Program, Carver College of Medicine, the University of Iowa, Iowa City, Iowa, USA.
Holden Comprehensive Cancer Center, Carver College of Medicine, the University of Iowa, Iowa City, Iowa, USA.
J Leukoc Biol. 2021 Oct;110(4):723-733. doi: 10.1002/JLB.5A0620-365R. Epub 2020 Dec 8.
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 CD56 NK had higher TIGIT and TIM3 expression than resting CD56 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.
抗 CD20 mAb 是大多数 B 细胞恶性肿瘤的有效治疗方法。检查点阻断已被用于增强 T 细胞介导的抗肿瘤反应。对于 NK 细胞表达的免疫检查点在基于抗 CD20 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 Raji B 细胞淋巴瘤细胞和来自正常供体的 PBMC 与利妥昔单抗 (RTX)、奥滨尤妥珠单抗 (OBZ) 或曲妥珠单抗（作为对照 mAb）在 20 h 至 9 d 之间进行共培养。RTX 和 OBZ 诱导 NK 细胞 T 细胞免疫受体与 Ig 和 ITIM 结构域（TIGIT）和 T 细胞免疫球蛋白粘蛋白-3（TIM3）的剂量依赖性上调，但不诱导 PD1、CTLA4 或 LAG3 的上调。尽管 TIGIT 和 TIM3 在两个亚群上均被上调，但静止 CD56 NK 的 TIGIT 和 TIM3 表达高于静止 CD56 NK。与来自 VF 或 FF 供体的 NK 细胞相比，具有 CD16 158VV 单核苷酸多态性的 NK 细胞具有更高的 TIM3 上调。与 TIGIT 或 TIM3 NK 细胞相比，TIGIT 和 TIM3 NK 细胞脱颗粒、产生细胞因子并表达激活标志物的程度更大。阻断 TIGIT、TIM3 或两者对 RTX 诱导的 NK 细胞增殖、脱颗粒、细胞因子产生或激活的影响很小。总之，TIGIT 和 TIM3 可作为抗 CD20 介导的 NK 细胞激活的标志物，但作为增强此类治疗抗肿瘤活性的靶点可能效果不佳。
