Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-β signaling

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外文摘要：Tumor-derived exosomes(TEXs)enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity.Chimeric antigen receptor(CAR)T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies,but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear.Here,we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19.However,lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1,TIM3,and LAG3 upon prolonged exposure.Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma.More importantly,single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell(Treg)phenotype conversion.By blocking transforming growth factor β(TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761,the negative effects of TEXs on Treg conversion,terminal differentiation,and immune checkpoint expression were rescued.Collectively,although TEXs lead to the initial activation of CAR T-cells,the effect of TEXs suppressed CAR T-cells,which can be rescued by LY2109761.A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

外文关键词：

tumor-derived exosomechimeric antigen receptor T-celllymphomaTGF-β

作者：

Yuanyuan Hao、Panpan Chen、Shanshan Guo、Mengyuan Li、Xueli Jin、Minghuan Zhang、Wenhai Deng、Ping Li、Wen Lei、Aibin Liang、Wenbin Qian

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作者单位：

Department of Hematology,The Second Affiliated Hospital,College of Medicine,Zhejiang University,Hangzhou 310009,China

Department of Hematology,Henan Provincial People's Hospital

Zhengzhou University People's Hospital,Zhengzhou 450003,China

Key Laboratory of Laboratory Medicine,Ministry of Education,School of Laboratory Medicine and Life Sciences,Wenzhou Medical University,Wenzhou 325000,China

Department of Hematology,Tongji Hospital of Tongji University,Shanghai 200065,China

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基金：

国家自然科学基金国家自然科学基金国家自然科学基金Science Technology Department of Zhejiang Province

项目编号：

8183000682170219818300042021C03117

出版年：

2024

DOI：

10.1007/s11684-023-1010-1

医学前沿

高等教育出版社

医学前沿

CSTPCD

影响因子：1.362

ISSN：2095-0217

年,卷(期)：2024.18(1)

参考文献量44