High CD62L expression predicts the generation of chimeric antigen receptor T cells with potent effector functions.

IF 4.8 4区 医学 Q2 IMMUNOLOGY
Hitomi Kasuya, Haosong Zhang, Yusuke Ito, Toshiaki Yoshikawa, Takahiro Nakashima, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya
{"title":"High CD62L expression predicts the generation of chimeric antigen receptor T cells with potent effector functions.","authors":"Hitomi Kasuya, Haosong Zhang, Yusuke Ito, Toshiaki Yoshikawa, Takahiro Nakashima, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya","doi":"10.1093/intimm/dxae015","DOIUrl":null,"url":null,"abstract":"<p><p>The efficient generation of chimeric antigen receptor (CAR) T cells is highly influenced by the quality of apheresed T cells. Healthy donor-derived T cells usually proliferate better than patients-derived T cells and are precious resources to generate off-the-shelf CAR-T cells. However, relatively little is known about the determinants that affect the efficient generation of CAR-T cells from healthy donor-derived peripheral blood mononuclear cells (PBMCs) compared with those from the patients' own PBMCs. We here examined the efficiency of CAR-T cell generation from multiple healthy donor samples and analyzed its association with the phenotypic features of the starting peripheral blood T cells. We found that CD62L expression levels within CD8+ T cells were significantly correlated with CAR-T cell expansion. Moreover, high CD62L expression within naïve T cells was associated with the efficient expansion of T cells with a stem cell-like memory phenotype, an indicator of high-quality infusion products. Intriguingly, genetic disruption of CD62L significantly impaired CAR-T cell proliferation and cytokine production upon antigen stimulation. Conversely, ectopic expression of a shedding-resistant CD62L mutant augmented CAR-T cell effector functions compared to unmodified CAR-T cells, resulting in improved antitumor activity in vivo. Collectively, we identified the surface expression of CD62L as a concise indicator of potent T-cell proliferation. CD62L expression is also associated with the functional properties of CAR-T cells. These findings are potentially applicable to selecting optimal donors to massively generate CAR-T cell products.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/intimm/dxae015","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

The efficient generation of chimeric antigen receptor (CAR) T cells is highly influenced by the quality of apheresed T cells. Healthy donor-derived T cells usually proliferate better than patients-derived T cells and are precious resources to generate off-the-shelf CAR-T cells. However, relatively little is known about the determinants that affect the efficient generation of CAR-T cells from healthy donor-derived peripheral blood mononuclear cells (PBMCs) compared with those from the patients' own PBMCs. We here examined the efficiency of CAR-T cell generation from multiple healthy donor samples and analyzed its association with the phenotypic features of the starting peripheral blood T cells. We found that CD62L expression levels within CD8+ T cells were significantly correlated with CAR-T cell expansion. Moreover, high CD62L expression within naïve T cells was associated with the efficient expansion of T cells with a stem cell-like memory phenotype, an indicator of high-quality infusion products. Intriguingly, genetic disruption of CD62L significantly impaired CAR-T cell proliferation and cytokine production upon antigen stimulation. Conversely, ectopic expression of a shedding-resistant CD62L mutant augmented CAR-T cell effector functions compared to unmodified CAR-T cells, resulting in improved antitumor activity in vivo. Collectively, we identified the surface expression of CD62L as a concise indicator of potent T-cell proliferation. CD62L expression is also associated with the functional properties of CAR-T cells. These findings are potentially applicable to selecting optimal donors to massively generate CAR-T cell products.

CD62L 的高表达预示着具有强大效应功能的嵌合抗原受体 T 细胞的产生。
嵌合抗原受体(CAR)T 细胞的高效生成在很大程度上受到无细胞捐献 T 细胞质量的影响。健康供体来源的T细胞通常比患者来源的T细胞增殖能力更强,是生成现成CAR-T细胞的宝贵资源。然而,与患者自身的外周血单核细胞(PBMC)相比,人们对影响从健康供体来源的外周血单核细胞(PBMC)高效生成 CAR-T 细胞的决定因素知之甚少。我们在此研究了从多个健康供体样本中生成 CAR-T 细胞的效率,并分析了其与起始外周血 T 细胞表型特征的关联。我们发现,CD8+ T 细胞中 CD62L 的表达水平与 CAR-T 细胞的扩增显著相关。此外,CD62L在幼稚T细胞中的高表达与具有干细胞记忆表型的T细胞的高效扩增有关,而干细胞记忆表型是高质量输注产品的指标。耐人寻味的是,CD62L的基因干扰会显著影响CAR-T细胞的增殖和抗原刺激时细胞因子的产生。相反,与未修饰的 CAR-T 细胞相比,异位表达抗脱落的 CD62L 突变体能增强 CAR-T 细胞的效应功能,从而提高体内的抗肿瘤活性。总之,我们发现 CD62L 的表面表达是 T 细胞有效增殖的简明指标。CD62L 的表达还与 CAR-T 细胞的功能特性有关。这些发现可能适用于选择最佳供体以大规模生成 CAR-T 细胞产品。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信