Identification of clonally expanded γδ T-cell populations during CAR-T cell therapy.

IF 3.2 4区 医学 Q3 CELL BIOLOGY Immunology & Cell Biology Pub Date : 2024-11-05 DOI:10.1111/imcb.12834
Arman Safavi, Jerome Samir, Mandeep Singh, Martina Bonomi, Raymond Yip Louie, Kenneth Micklethwaite, Fabio Luciani
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Abstract

Anti-CD19 Chimeric Antigen Receptor (CAR)-T cell therapies have shown promise for treating B cell malignancies, but the clinical outcome is influenced by both the CAR-T product and the patient's immune system. The role of γδ T cells in the context of CAR-T cell therapy remains poorly understood. This study investigates the transcriptional heterogeneity, clonal expansion and dynamics of γδ T cells in patients undergoing anti-CD19 CAR-T cell therapy. Longitudinal single cell multi-omics analysis was performed on γδ T cells from four patients receiving anti-CD19 CAR-T cell therapy. Single cell RNA-seq, antibody-based protein profiling (AbSeq) and full-length TCRγδ sequences revealed clonally expanded populations displaying plasticity in T cell differentiation, and temporal dynamics of large clones, suggesting ongoing expansion and differentiation. Clonally expanded γδ T cells had heterogeneous gene expression profiles, occupying seven transcriptionally distinct clusters. Analysis of chemokine markers indicated cluster-specific homing tendencies of circulating γδ T cells to peripheral tissues. We found unexpectedly high frequencies of Vδ1 and Vδ3 cells in the blood with distinct gene and protein expression profiles. This analysis provides insights into the dynamic and heterogeneous nature of γδ T cells following anti-CD19 CAR-T cell therapy, contributing valuable information for optimizing CAR-T cell therapies in B cell malignancies.

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识别 CAR-T 细胞疗法中克隆扩增的 γδ T 细胞群。
抗CD19嵌合抗原受体(CAR)-T细胞疗法已显示出治疗B细胞恶性肿瘤的前景,但临床结果受CAR-T产品和患者免疫系统的影响。γδT细胞在CAR-T细胞疗法中的作用仍鲜为人知。本研究调查了接受抗CD19 CAR-T细胞治疗的患者体内γδT细胞的转录异质性、克隆扩增和动态变化。对接受抗 CD19 CAR-T 细胞疗法的四名患者的 γδ T 细胞进行了纵向单细胞多组学分析。单细胞 RNA-seq、基于抗体的蛋白质分析(AbSeq)和全长 TCRγδ 序列揭示了克隆扩增的群体,显示了 T 细胞分化的可塑性,以及大克隆的时间动态性,表明了持续的扩增和分化。克隆扩增的γδT细胞具有异质性基因表达谱,占据了七个转录不同的集群。趋化因子标记物的分析表明,循环中的γδT细胞具有向外周组织归巢的特异性集群倾向。我们意外地发现,血液中的 Vδ1 和 Vδ3 细胞频率很高,而且基因和蛋白表达谱截然不同。这项分析深入揭示了抗CD19 CAR-T细胞疗法后γδT细胞的动态和异质性,为优化B细胞恶性肿瘤的CAR-T细胞疗法提供了有价值的信息。
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来源期刊
Immunology & Cell Biology
Immunology & Cell Biology 医学-免疫学
CiteScore
7.50
自引率
2.50%
发文量
98
审稿时长
4-8 weeks
期刊介绍: The Australasian Society for Immunology Incorporated (ASI) was created by the amalgamation in 1991 of the Australian Society for Immunology, formed in 1970, and the New Zealand Society for Immunology, formed in 1975. The aim of the Society is to encourage and support the discipline of immunology in the Australasian region. It is a broadly based Society, embracing clinical and experimental, cellular and molecular immunology in humans and animals. The Society provides a network for the exchange of information and for collaboration within Australia, New Zealand and overseas. ASI members have been prominent in advancing biological and medical research worldwide. We seek to encourage the study of immunology in Australia and New Zealand and are active in introducing young scientists to the discipline.
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