The redirected killing of PD-L1 positive tumor cells by the expanded mucosa-associated invariant T (MAIT) cells is mediated with a bispecific antibody targeting TCR Vα7.2 and PD-L1
The redirected killing of PD-L1 positive tumor cells by the expanded mucosa-associated invariant T (MAIT) cells is mediated with a bispecific antibody targeting TCR Vα7.2 and PD-L1
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扩大的粘膜相关不变 T (MAIT) 细胞对 PD-L1 阳性肿瘤细胞的重定向杀伤是由针对 TCR Vα7.2 和 PD-L1 的双特异性抗体介导的
DOI：
10.1016/j.bbrc.2023.01.006
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发表时间：
2023
影响因子：
3.1
通讯作者：
Zhou Pengfei
中科院分区：
文献类型：
--
作者：
Yang Rui;He Qing;Zhang Jing;Yan Yongxiang;Shi Jian;Zhou Pengfei
以CD3为基础的T细胞结合分子靶向PAN-T细胞，带来了血液肿瘤的程序化治疗和管理。然而，这些模式已被证明可以激发所有类型的T细胞，导致细胞因子风暴综合征，并激活Treg细胞。因此，调节和增强特定T细胞亚群的抗肿瘤反应是受到鼓励的。我们初步发现，平板固定化V-α7.2mAb(Clone 3C10)与IL-2+IL-15结合可扩增出高纯度的黏膜相关不变T细胞。然后，我们制备了一种新型的抗Vα7.2TCRbsAb，Vα7.2x PD-L1，以激活这些扩增的MAIT细胞的抗肿瘤活性。此外，我们的研究结果表明，Vα7.2x PD-L1可以介导MAIT细胞与肿瘤细胞之间的细胞间连接，选择性地诱导扩增的MAIT细胞在只有靶细胞存在的情况下激活、产生细胞因子、脱颗粒和细胞毒作用。总而言之，这项概念验证研究提供了一种新的工具来探索MAIT细胞在对抗PD-L1阳性实体瘤方面的临床潜力，并建议进一步鼓励设计针对TCRα链特异性先天T细胞亚群的新型T细胞订户，而不是PAN CD3+T细胞。
Pan-T cell targeting by CD3-based T cell engagers has brought program-shift treatment and management of blood tumors. However, these modalities have been shown to provoke all types of T cells leading to cytokine storm syndrome, and activate Treg cells. Thus, modulating and potentiating the antitumor responses of a specific T cell subset was encouraged. We initially found that high purity of mucosa-associated invariant T (MAIT) cells could be expanded by the combination of plate-immobilized Vα7.2 mAb (Clone 3C10) and IL2 plus IL15. Then, we generated a novel anti-Vα7.2 TCR bsAb, Vα7.2 x PD-L1, to invoke the anti-tumor potency of these expanded MAIT cells. Furthermore, our data have demonstrated that Vα7.2 x PD-L1 could mediate the cell-to-cell conjunction between MAIT cell and tumor cell line, selectively elicit the activation, cytokine production, degranulation, and cytotoxicity of the expanded MAIT cells in the presence of target cell only. Collectively, this proof-of-concept study provides a new tool to explore the clinical potential of MAIT cells in fighting against PD-L1 positive solid tumors and suggests additional encouragement in designing novel T cell engagers targeting TCR alpha chain specific innate-like T cells subsets, other than pan CD3+T cells.