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4-1BB与DAP10的组合可促进NKG2D(bbz)嵌合抗原受体T细胞（CAR-T细胞）的增殖和存活。

Combination of 4-1BB and DAP10 promotes proliferation and persistence of NKG2D(bbz) CAR-T cells.

作者信息

Wei Cheng, Xia Kangfu, Xie Yucheng, Ye Sishi, Ding Yanghui, Liu Zairu, Zheng Rong, Long Jing, Wei Qinchuan, Li Yumei, Yang Dongxia, Xu Xiaojun, Zhao Ai, Gao Jimin

机构信息

Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.

Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, China.

出版信息

Front Oncol. 2022 Jul 29;12:893124. doi: 10.3389/fonc.2022.893124. eCollection 2022.

DOI:10.3389/fonc.2022.893124
PMID:35965586
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9372572/
Abstract

Chimeric antigen receptor (CAR)-T cell therapy has been shown to have considerable therapeutic effects in hematological malignancies, and NKG2D(z) CAR-T cell therapy has been verified to be safe based on clinical trials. However, due to the poor persistence of NKG2D(z) CAR-T cells, their therapeutic effect is not obvious. Here, we constructed NKG2D(bbz) CAR-T cells that can simultaneously activate 4-1BB and DAP10 costimulatory signaling. They were found to be cytotoxic to the target cells and . They exhibited low differentiation, low exhaustion, and good proliferation. Importantly, the proportions of central memory T (Tcm) and stem cell-like memory T (Tscm) cell subsets were strikingly increased. After long-term incubation with the target cells, they displayed reduced exhaustion compared to NKG2D(z) CAR-T cells. Further, in the presence of the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, they exhibited reduced exhaustion and apoptosis, upregulated Bcl2 expression, and an increased proportion of Tcm cell subsets. Finally, NKG2D(bbz) CAR-T cells had better antitumor effects . In summary, the results showed that NKG2D(bbz) CAR-T cells may be valuable for cellular immunotherapy of cancer.

摘要

嵌合抗原受体（CAR）-T细胞疗法已被证明在血液系统恶性肿瘤中具有显著的治疗效果，并且基于临床试验，NKG2D(z) CAR-T细胞疗法已被证实是安全的。然而，由于NKG2D(z) CAR-T细胞的持久性较差，其治疗效果并不明显。在此，我们构建了能同时激活4-1BB和DAP10共刺激信号的NKG2D(bbz) CAR-T细胞。发现它们对靶细胞具有细胞毒性，且表现出低分化、低耗竭和良好的增殖能力。重要的是，中央记忆T（Tcm）细胞和干细胞样记忆T（Tscm）细胞亚群的比例显著增加。与靶细胞长期孵育后，与NKG2D(z) CAR-T细胞相比，它们表现出更低的耗竭水平。此外，在存在磷酸肌醇3-激酶（PI3K）抑制剂LY294002的情况下，它们表现出更低的耗竭和凋亡水平，Bcl2表达上调，且Tcm细胞亚群比例增加。最后，NKG2D(bbz) CAR-T细胞具有更好的抗肿瘤效果。总之，结果表明NKG2D(bbz) CAR-T细胞可能对癌症的细胞免疫治疗具有重要价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/4c3532980eec/fonc-12-893124-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/8a9e6646f1dc/fonc-12-893124-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/7efd4fa8e37c/fonc-12-893124-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/d32e98f92db2/fonc-12-893124-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/6b7c26f190a8/fonc-12-893124-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/56fa8cae3c7d/fonc-12-893124-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/4c3532980eec/fonc-12-893124-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/8a9e6646f1dc/fonc-12-893124-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/7efd4fa8e37c/fonc-12-893124-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/d32e98f92db2/fonc-12-893124-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/6b7c26f190a8/fonc-12-893124-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/56fa8cae3c7d/fonc-12-893124-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/787b/9372572/4c3532980eec/fonc-12-893124-g006.jpg

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