活细胞糖萼工程的比较机制研究：改善B淋巴瘤的过继细胞治疗

IF 11.6 1区工程技术 Q1 ENGINEERING, MULTIDISCIPLINARY

Engineering Pub Date : 2025-09-04 DOI:10.1016/j.eng.2025.08.037

Yuxin Li, Tao Gao, Zhaoxin Han, Valeria M. Stepanova, Han Wang, Hongmin Chen, Alexey Stepanov, Senlian Hong

{"title":"活细胞糖萼工程的比较机制研究：改善B淋巴瘤的过继细胞治疗","authors":"Yuxin Li, Tao Gao, Zhaoxin Han, Valeria M. Stepanova, Han Wang, Hongmin Chen, Alexey Stepanov, Senlian Hong","doi":"10.1016/j.eng.2025.08.037","DOIUrl":null,"url":null,"abstract":"Adoptive cell therapies (ACTs) have achieved remarkable clinical success in treating cancers; however, their broader application is greatly impeded by high cost and restricted antigen specificity. Recently, engineering the glycocalyx has provided a convenient transgene-free means to design ACTs with high-avidity glycan ligands to target CD22, offering a new avenue for B lymphoma immunotherapy. In this work, we perform a comparative analysis of the molecular profiles involved in metabolic or chemoenzymatic glycocalyx engineering and explore their multiplexing capability. The glycoproteomic results revealed content-dependent customization of the NK-92MI glycocalyx. Compared with metabolic engineering, exogenous chemoenzymatic engineering has comparable or even superior ligand-loading efficiency, with some immune synapse components modified to facilitate their spatial recognition against target cells. Next, we tested the orthogonal creation of ligands on natural killer (NK)-92MI cells by further engineering α2,3-sialylated N-acetyllactosamine moieties to produce selectin ligands that are essential for better in vivo eradication of mouse xenograft B lymphoma. Finally, we demonstrate that analogous engineering of CD19-targeted chimeric antigen receptor T (CAR-T) cells to produce CD19/CD22 bitargeted therapy can enhance antigen targeting and tumor cell killing, offering an alternative cost-efficient agent for treating cancer relapse with decreased levels of CD19 antigens. These findings establish a mechanistic foundation for glycocalyx engineering and support the rational design of next-generation ACTs against B lymphoma.","PeriodicalId":11783,"journal":{"name":"Engineering","volume":"34 1","pages":""},"PeriodicalIF":11.6000,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Comparative Mechanistic Study of Live-Cell Glycocalyx Engineering: Improving Adoptive Cell Therapies Against B Lymphoma\",\"authors\":\"Yuxin Li, Tao Gao, Zhaoxin Han, Valeria M. Stepanova, Han Wang, Hongmin Chen, Alexey Stepanov, Senlian Hong\",\"doi\":\"10.1016/j.eng.2025.08.037\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Adoptive cell therapies (ACTs) have achieved remarkable clinical success in treating cancers; however, their broader application is greatly impeded by high cost and restricted antigen specificity. Recently, engineering the glycocalyx has provided a convenient transgene-free means to design ACTs with high-avidity glycan ligands to target CD22, offering a new avenue for B lymphoma immunotherapy. In this work, we perform a comparative analysis of the molecular profiles involved in metabolic or chemoenzymatic glycocalyx engineering and explore their multiplexing capability. The glycoproteomic results revealed content-dependent customization of the NK-92MI glycocalyx. Compared with metabolic engineering, exogenous chemoenzymatic engineering has comparable or even superior ligand-loading efficiency, with some immune synapse components modified to facilitate their spatial recognition against target cells. Next, we tested the orthogonal creation of ligands on natural killer (NK)-92MI cells by further engineering α2,3-sialylated N-acetyllactosamine moieties to produce selectin ligands that are essential for better in vivo eradication of mouse xenograft B lymphoma. Finally, we demonstrate that analogous engineering of CD19-targeted chimeric antigen receptor T (CAR-T) cells to produce CD19/CD22 bitargeted therapy can enhance antigen targeting and tumor cell killing, offering an alternative cost-efficient agent for treating cancer relapse with decreased levels of CD19 antigens. These findings establish a mechanistic foundation for glycocalyx engineering and support the rational design of next-generation ACTs against B lymphoma.\",\"PeriodicalId\":11783,\"journal\":{\"name\":\"Engineering\",\"volume\":\"34 1\",\"pages\":\"\"},\"PeriodicalIF\":11.6000,\"publicationDate\":\"2025-09-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Engineering\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://doi.org/10.1016/j.eng.2025.08.037\",\"RegionNum\":1,\"RegionCategory\":\"工程技术\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENGINEERING, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Engineering","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1016/j.eng.2025.08.037","RegionNum":1,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, MULTIDISCIPLINARY","Score":null,"Total":0}

引用次数: 0

摘要

过继细胞疗法（ACTs）在治疗癌症方面取得了显著的临床成功；然而，它们的广泛应用受到高成本和抗原特异性限制的极大阻碍。近年来，对糖萼进行工程化设计，为设计靶向CD22的高亲和力聚糖配体ACTs提供了一种方便的无转基因手段，为B淋巴瘤免疫治疗提供了新的途径。在这项工作中，我们对参与代谢或化学酶糖萼工程的分子谱进行了比较分析，并探索了它们的多路复用能力。糖蛋白组学结果揭示了NK-92MI糖萼的含量依赖性定制。与代谢工程相比，外源性化学酶工程具有相当甚至更高的配体负载效率，通过修饰一些免疫突触成分以促进其对靶细胞的空间识别。接下来，我们通过进一步设计α2,3-唾液化的n -乙酰乳胺片段，在自然杀伤(NK)-92MI细胞上正交制备配体，以获得更好地在体内根除小鼠异种移植B淋巴瘤所必需的选择素配体。最后，我们证明了类似的CD19靶向嵌合抗原受体T （CAR-T）细胞工程产生CD19/CD22靶向治疗可以增强抗原靶向和肿瘤细胞杀伤，为治疗CD19抗原水平降低的癌症复发提供了一种替代的经济有效的药物。这些发现为糖萼工程奠定了机制基础，并为合理设计下一代抗B淋巴瘤ACTs提供了支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

A Comparative Mechanistic Study of Live-Cell Glycocalyx Engineering: Improving Adoptive Cell Therapies Against B Lymphoma

Adoptive cell therapies (ACTs) have achieved remarkable clinical success in treating cancers; however, their broader application is greatly impeded by high cost and restricted antigen specificity. Recently, engineering the glycocalyx has provided a convenient transgene-free means to design ACTs with high-avidity glycan ligands to target CD22, offering a new avenue for B lymphoma immunotherapy. In this work, we perform a comparative analysis of the molecular profiles involved in metabolic or chemoenzymatic glycocalyx engineering and explore their multiplexing capability. The glycoproteomic results revealed content-dependent customization of the NK-92MI glycocalyx. Compared with metabolic engineering, exogenous chemoenzymatic engineering has comparable or even superior ligand-loading efficiency, with some immune synapse components modified to facilitate their spatial recognition against target cells. Next, we tested the orthogonal creation of ligands on natural killer (NK)-92MI cells by further engineering α2,3-sialylated N-acetyllactosamine moieties to produce selectin ligands that are essential for better in vivo eradication of mouse xenograft B lymphoma. Finally, we demonstrate that analogous engineering of CD19-targeted chimeric antigen receptor T (CAR-T) cells to produce CD19/CD22 bitargeted therapy can enhance antigen targeting and tumor cell killing, offering an alternative cost-efficient agent for treating cancer relapse with decreased levels of CD19 antigens. These findings establish a mechanistic foundation for glycocalyx engineering and support the rational design of next-generation ACTs against B lymphoma.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Engineering Environmental Science-Environmental Engineering

自引率

1.60%

发文量

335

审稿时长

35 days

期刊介绍： Engineering, an international open-access journal initiated by the Chinese Academy of Engineering (CAE) in 2015, serves as a distinguished platform for disseminating cutting-edge advancements in engineering R&D, sharing major research outputs, and highlighting key achievements worldwide. The journal's objectives encompass reporting progress in engineering science, fostering discussions on hot topics, addressing areas of interest, challenges, and prospects in engineering development, while considering human and environmental well-being and ethics in engineering. It aims to inspire breakthroughs and innovations with profound economic and social significance, propelling them to advanced international standards and transforming them into a new productive force. Ultimately, this endeavor seeks to bring about positive changes globally, benefit humanity, and shape a new future.