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

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

机构地区：[1]Department of Hematology,The Second Affiliated Hospital,College of Medicine,Zhejiang University,Hangzhou,310009,China [2]Department of Hematology,Henan Provincial People’s Hospital,Zhengzhou University People’s Hospital,Zhengzhou,450003,China [3]Key Laboratory of Laboratory Medicine,Ministry of Education,School of Laboratory Medicine and Life Sciences,Wenzhou Medical University,Wenzhou,325000,China [4]Department of Hematology,Tongji Hospital of Tongji University,Shanghai,200065,China

出　　处：《Frontiers of Medicine》2024年第1期128-146,共19页医学前沿（英文版）

基　　金：supported by the funds from the National Natural Science Foundation of China(Nos.81830006,82170219,and 81830004);the Science Technology Department of Zhejiang Province(No.2021C03117).

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.

关 键 词：tumor-derived exosome chimeric antigen receptor T-cell lymphoma TGF-Β 

分 类 号：R733.4[医药卫生—肿瘤]