Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, 266021, China.
Clinical Laboratory, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University, Qingdao, China.
Cancer Immunol Immunother. 2020 Dec;69(12):2571-2587. doi: 10.1007/s00262-020-02638-0. Epub 2020 Jun 25.
As ideal cells that can be used for adoptive cell therapy, γδ T cells are a group of homogeneous cells with high proliferative and tumor killing ability. However, γδ T cells are apt to apoptosis and show decreased cytotoxicity under persistent stimulation in vitro and cannot aggregate at tumor sites efficiently in vivo, both of which are two main obstacles to tumor adoptive immunotherapy. In this study, we found that the immune checkpoint T-cell immunoglobulin domain and mucin domain 3 (TIM-3) were up-regulated significantly on γδ T cells during their ex vivo expansion and this up-regulation contributed to the dysfunction of γδ T cells. Although the killing ability of γδ T cells against breast cancer cells which exhibited a high level of epithelial cell adhesion molecule (EpCAM) was enhanced, the level of TIM-3 on γδ T cells was also further up-regulated under the application of the bispecific antibody MT110 (anti-CD3 × anti-EpCAM) which can redirect T cells to target cells. Besides, these γδ T cells with up-regulated TIM-3 exhibited an increased susceptibility to apoptosis. By reinvigorating dysfunctional γδ T cells and promoting them to accumulate at tumor sites, the combined use of TIM-3 inhibitor and MT110 could further enhance the anti-tumor effect of the adoptively transfused γδ T cells. These results may have clinical implications for the design of new translational anti-tumor regimens aimed at combining checkpoint blockade and immune cell redirection.
作为可用于过继细胞治疗的理想细胞，γδ T 细胞是一群具有高增殖和肿瘤杀伤能力的同质细胞。然而，γδ T 细胞在体外持续刺激下容易凋亡，并且在体内不能有效地聚集在肿瘤部位，这两者都是肿瘤过继免疫治疗的两个主要障碍。在这项研究中，我们发现 γδ T 细胞在体外扩增过程中免疫检查点 T 细胞免疫球蛋白结构域和粘蛋白结构域 3（TIM-3）显著上调，这种上调导致了 γδ T 细胞的功能障碍。尽管 γδ T 细胞对表现出高水平上皮细胞黏附分子（EpCAM）的乳腺癌细胞的杀伤能力增强，但在可以将 T 细胞重新导向靶细胞的双特异性抗体 MT110（抗-CD3×抗-EpCAM）的应用下，γδ T 细胞上 TIM-3 的水平也进一步上调。此外，这些上调 TIM-3 的 γδ T 细胞对凋亡的敏感性增加。通过重新激活功能失调的 γδ T 细胞并促进它们在肿瘤部位聚集，TIM-3 抑制剂和 MT110 的联合使用可以进一步增强过继输注的 γδ T 细胞的抗肿瘤作用。这些结果可能对设计旨在结合检查点阻断和免疫细胞重定向的新型转化抗肿瘤方案具有临床意义。
