CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
抗 PD-L1 × 抗 CD3 双特异性 T 细胞衔接器武装的 T 细胞可以克服免疫抑制，并重定向 T 细胞杀伤表达 PD-L1 的乳腺癌细胞
英文原题：Anti-PD-L1 × anti-CD3 bispecific T-cell engager-armed T cells can overcome immunosuppression and redirect T cells to kill breast cancer cells expressing PD-L1.
查看英文原题
Anti-PD-L1 × anti-CD3 bispecific T-cell engager-armed T cells can overcome immunosuppression and redirect T cells to kill breast cancer cells expressing PD-L1.
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中文摘要
基于T细胞的免疫治疗已经改变了癌症治疗格局。然而，T细胞的抗肿瘤活性可被肿瘤细胞表达的免疫检查点分子程序性死亡配体1（PD-L1）所抑制，PD-L1与T细胞上的PD-1相互作用。
我们制备了αPD-L1 × αCD3双特异性T细胞衔接器武装的T细胞（BATs），以阻断PD-L1/PD-1相互作用，从而重定向T细胞杀伤肿瘤细胞。αPD-L1 × αCD3双特异性T细胞衔接器（BTEs）由中国仓鼠卵巢（CHO）细胞生产，用于武装人原代T细胞。采用流式细胞术研究BTE与BATs的结合。在二维（2D）和三维（3D）培养模型中评估BATs对表达PD-L1的乳腺癌（BC）细胞系的细胞毒性。还检测了BTE在BATs上的结合稳定性及其冻存后的疗效。CHO细胞BTE表达产量为3.34 mg/ml。其在T细胞上的结合能力达到91.02 ± 4.2 %。BATs特异性裂解表达PD-L1的BC细胞，在10:1效靶比下，HCC70细胞裂解率为56.4 ± 15.3 %，MDA-MB-231细胞裂解率为70.67 ± 15.6 %。BATs对PD-L1阴性BC细胞MCF-7和T47D仅显示轻微且无显著意义的裂解。
此外，BATs在共培养48和72 h后显著破坏表达PD-L1的MDA-MB-231 3D球体。冻存的BATs维持了BTE结合稳定性、细胞活力和抗癌活性，与新鲜BATs相当。αPD-L1 × αCD3 BATs在2D和3D共培养试验中诱导了表达PD-L1的BC细胞的细胞裂解。BATs可以制备并保存，便于其使用和运输。
本研究证明了αPD-L1 × αCD3 BATs在治疗PD-L1阳性表达癌症中的潜力。
展开英文摘要原文
T cell-based immunotherapy has transformed cancer treatment. Nonetheless, T cell antitumor activity can be inhibited by an immune checkpoint molecule expressed on cancer cells, program death ligand 1 (PD-L1), which interacts with the PD-1 on T cells.
We generated αPD-L1 × αCD3 bispecific T-cell engager-armed T cells (BATs) to prevent PD-L1/PD-1 interaction and hence to redirect T cells to kill cancer cells. αPD-L1 × αCD3 bispecific T-cell engagers (BTEs) were produced from Chinese hamster ovary (CHO) cells to arm human primary T cells. Flow cytometry was used to investigate BTE binding to BATs. The cytotoxicity of BATs against PD-L1-expressing breast cancer (BC) cell lines was assessed in 2-dimensional (2D) and 3-dimensional (3D) culture models.
The binding stability of BTE on BATs and their efficacy after cryopreservation were also examined. The CHO cell BTE expression yield was 3. 34 mg/ml. The binding ability on T cells reached 91. 02 ± 4. 2 %. BATs specifically lysed PD-L1-expressing BC cells, with 56. 4 ± 15. 3 % HCC70 cells and 70. 67 ± 15. 6 % MDA-MB-231 cells lysed at a 10:1 effector-to-target ratio. BATs showed slight, nonsignificant lysis of PD-L1-negative BC cells, MCF-7, and T47D.
Moreover, BATs significantly disrupted MDA-MB-231 3D spheroids expressing PD-L1 after 48 and 72 h of coculture. Cryopreserved BATs maintained BTE binding stability, cell viability, and anticancer activity, comparable to fresh BATs. αPD-L1 × αCD3 BATs induced the cytolysis of PD-L1-expressing BC cells in 2D and 3D coculture assays. BATs can be prepared and preserved, facilitating their use and transportation.
This study demonstrates the potential of αPD-L1 × αCD3 BATs in treating cancers with positive PD-L1 expression.
论文信息
- 作者
- Luangwattananun P、Sangsuwannukul T、Supimon K、Thuwajit C、Chieochansin T、Sa-Nguanraksa D、Samarnthai N、O-Charoenrat P
- 第一作者单位
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.Thailand
- 通讯作者单位
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Electronic address: pathai.yen@mahidol.edu.Thailand
- 期刊
- International immunopharmacology2023 Nov
- 原文标识
- PubMed 37804657 · DOI 10.1016/j.intimp.2023.111012