Adoptive cell therapy using patients' own T‐cells is expected to be an ideal cancer treatment strategy with excellent antitumor effects and low side effects. However, this therapy targeting solid tumors is unlikely to be effective because tumor tissues have an environment that suppresses T‐cell function. In particular, interaction between programmed death‐1 (PD‐1) and its ligand (PD‐L1) inhibits T‐cell activation by which T‐cells eliminate tumor cells. Here, we attempted to develop T‐cells that can exert potent antitumor activity even in tumor tissues by genetically modifying them to express the anti‐PD‐L1 membrane‐anchoring type single chain variable fragment (M‐scFv) that can inhibit PD‐L1/PD‐1 interaction. Anti‐PD‐L1 M‐scFv could be expressed on T‐cells while maintaining PD‐L1‐binding ability. Although T‐cell proliferation induced by CD3 stimulation was decreased depending on the PD‐L1 stimulation intensity, M‐scFv‐expressing T‐cells showed high proliferative activity even in the presence of PD‐L1 by avoiding the PD‐L1/PD‐1‐mediated suppression. Furthermore, M‐scFv‐expressing T‐cells showed higher cytotoxic activity against PD‐L1high tumor cells than that of mock T‐cells. The effect of PD‐L1/PD‐1 blockade was more pronounced when the therapeutic target was low‐antigenic tumor cells with low major histocompatibility complex expression, presenting only the shared antigen. These results indicated that anti‐PD‐L1 M‐scFv expression was functional in avoiding T‐cell dysfunction by PD‐L1/PD‐1 interaction. Our concept of anti‐PD‐L1 M‐scFv‐expressing T‐cells is thus expected to improve the efficacy of T‐cell therapy and contribute to simplify the treatment system and reduce treatment costs compared with the combination therapy of T‐cells and antibodies.

中文翻译：

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一种具有免疫检查点抑制能力的抗癌T细胞药物的开发及功能分析

使用患者自身 T 细胞的过继细胞疗法有望成为一种理想的癌症治疗策略，具有优异的抗肿瘤作用和低副作用。然而，这种针对实体瘤的疗法不太可能有效，因为肿瘤组织具有抑制 T 细胞功能的环境。特别是，程序性死亡-1 (PD-1) 与其配体 (PD-L1) 之间的相互作用抑制了 T 细胞活化，从而使 T 细胞消除了肿瘤细胞。在这里，我们试图开发出即使在肿瘤组织中也能发挥有效抗肿瘤活性的 T 细胞，方法是对它们进行基因改造，以表达可抑制 PD-L1 的抗 PD-L1 膜锚定型单链可变片段 (M-scFv) /PD-1 相互作用。抗 PD-L1 M-scFv 可以在 T 细胞上表达，同时保持 PD-L1 结合能力。尽管 CD3 刺激诱导的 T 细胞增殖根据 PD-L1 刺激强度而降低，但表达 M-scFv 的 T 细胞即使在存在 PD-L1 的情况下也通过避免 PD-L1/PD-1 显示出高增殖活性介导的抑制。此外，与模拟 T 细胞相比，表达 M-scFv 的 T 细胞对 PD-L1 高肿瘤细胞显示出更高的细胞毒活性。当治疗靶点是主要组织相容性复合体表达低的低抗原性肿瘤细胞时，PD-L1/PD-1 阻断的效果更明显，仅呈递共享抗原。这些结果表明，抗 PD-L1 M-scFv 表达在通过 PD-L1/PD-1 相互作用避免 T 细胞功能障碍方面发挥作用。