肿瘤细胞治疗研究
英文原题：TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength.
TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength.
T细胞亲和力是过继性T细胞疗法（ACT）治疗癌症疗效的主要决定因素。
T细胞亲和力是过继性T细胞疗法（ACT）治疗癌症疗效的主要决定因素。然而，高亲和力肿瘤特异性T细胞很少能从癌症患者中分离出来，这凸显了需要增强低亲和力细胞毒性能力的策略。在此，我们通过敲除TIGIT——一种在浸润胃肠道肿瘤的耗竭CD8+ T细胞上表达的关键抑制性分子——挽救了低亲和力T细胞对胰腺导管腺癌（PDAC）的抗肿瘤功能。我们发现，通过碱基编辑破坏TIGIT可增强由弱T细胞受体（TCR）接合引发的细胞内信号转导，从而强化细胞骨架重排，进而提高T细胞亲和力并稳定免疫突触。因此，TIGIT破坏使低亲和力T细胞能够发挥强大的脱颗粒作用，与高亲和力T细胞相当，并在雄性小鼠体内表现出强效且持久的抗肿瘤能力。这些结果凸显了TIGIT敲除作为增强低亲和力T细胞功能并拓宽TCR工程化T细胞在胰腺癌及其他实体恶性肿瘤治疗中应用范围的潜在策略。
T-cell avidity is a major determinant of Adoptive T cell therapy (ACT) efficacy for cancer treatment. However, high-avidity tumor-specific T cells can rarely be isolated from cancer patients, highlighting the need for strategies to enhance the cytotoxic capacity of low-avidity cells. Here, we rescue the anti-tumor functions of low-avidity T cells against pancreatic ductal adenocarcinoma (PDAC) by knocking-out TIGIT, a key inhibitory molecule expressed on exhausted CD8 + T cells infiltrating gastrointestinal tumors. We uncover that TIGIT disruption by base editing boosts the intracellular signal transduction derived from a weak T cell receptor (TCR) engagement enforcing cytoskeletal rearrangements, thus increasing T cell avidity and stabilizing the immunological synapse. Accordingly, TIGIT disruption enables low-avidity T cells to exert robust degranulation, comparable to that of high-avidity T cells, and potent and durable anti-tumor capacity in vivo in male mice. These results highlight TIGIT knockout as a potential strategy to enhance low-avidity T cell function and broaden the repertoire of TCR engineered T cells in the treatment of pancreatic cancer and other solid malignancies.
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