γδ T 细胞调节小细胞肺癌中的抗肿瘤免疫
γδ T cells modulate anti-tumor immunity in small cell lung cancer.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
用靶向肿瘤细胞的抗体对γδ T 细胞进行化学工程改造以增强肿瘤免疫治疗
英文原题：Chemical engineering of γδ T cells with cancer cell-targeting antibodies for enhanced tumor immunotherapy.
查看英文原题
Chemical engineering of γδ T cells with cancer cell-targeting antibodies for enhanced tumor immunotherapy.
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中文摘要
γδ T 细胞在过继性细胞治疗中具有巨大前景，但存在肿瘤靶向效率低的问题。在此，我们报道了抗体-γδ T 细胞偶联物的开发，用于增强肿瘤治疗。通过评估位于细胞表面的不同生物分子，唾液酸——多种细胞表面聚糖的末端糖——被鉴定为通过代谢聚糖标记将抗体锚定到 γδ T 细胞上的最佳位点，该方法使用含有生物正交官能团的非天然糖。将程序性死亡配体 1（PD-L1）特异性纳米抗体（αPD-L1）通过点击化学偶联到 γδ T 细胞上，所得的 αPD-L1-γδ T 细胞对 PD-L1 阳性癌细胞系、患者来源的原代癌细胞以及活体小鼠中的异种移植肿瘤表现出增强的细胞毒性。在机制上，αPD-L1-γδ T 细胞通过结合 PD-L1 靶向癌细胞和肿瘤，并诱导癌细胞焦亡。
此外，αPD-L1-γδ T 细胞重塑肿瘤微环境使其具有免疫活性，至少部分是通过 CCR5/CCL5 轴招募和激活 CD8 + T 细胞实现的。这项工作为 γδ T 细胞的化学工程提供了一种通用策略，以改善其治疗应用。
展开英文摘要原文
Gamma delta (γδ) T cells hold great promise in adoptive cell therapy, but suffer from low tumor-targeting efficiency.
Herein, we report the development of antibody-γδ T cell conjugates for enhanced tumor therapy. By evaluating different biomolecules residing on the cell surface, sialic acids-the terminal sugars of various cell-surface glycans-are identified as the optimum site for anchoring antibodies onto γδ T cells via metabolic glycan labeling with unnatural sugars containing a bioorthogonal functional group.
A programmed death-ligand 1 (PD-L1)-specific nanobody (αPD-L1) is conjugated onto γδ T cells via click chemistry and the resulting αPD-L1-γδ T cells exhibit enhanced cytotoxicity towards PD-L1-positive cancer cell lines, patient-derived primary cancer cells, and xenografted tumors in living mice.
Mechanistically, αPD-L1-γδ T cells target cancer cells and tumors via binding to PD-L1 and induce cancer cell pyroptosis.
Furthermore, αPD-L1-γδ T cells remodel the tumor microenvironment to be immune-active, at least partially through the recruitment and activation of CD8 + T cells via the CCR5/CCL5 axis. This work provides a versatile strategy for chemical engineering of γδ T cells for improved therapeutic applications.
论文信息
- 作者
- Chen L、Cheng B、Yang Z、Zheng M、Chu T、Wang P、He T、Xue Y
- 单位
- Department of Pharmacy, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing 100191, China.China
- 期刊
- National science review2025 Aug
- 原文标识
- PubMed 40842867 · DOI 10.1093/nsr/nwaf256
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