Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia
Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia
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DOI：
10.1016/j.ymthe.2020.12.033
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发表时间：
2021-04-07
影响因子：
12.4
通讯作者：
Kenderian, Saad S.
中科院分区：
文献类型：
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作者：
Cox, Michelle J.;Lucien, Fabrice;Kenderian, Saad S.
嵌合抗原受体（CAR） T细胞治疗在一些血液系统恶性肿瘤患者中取得了前所未有的效果；然而，肿瘤微环境的抑制阻碍了CART细胞治疗的更广泛成功。我们以慢性淋巴细胞白血病（CLL）为模型，研究肿瘤微环境与CART细胞之间的相互作用。CLL的特点是免疫抑制微环境，大量的全身细胞外囊泡（ev），以及对CART细胞治疗的相对较低的持久反应率。在这项研究中，我们对未经治疗的CLL患者的血浆EVs进行了表征，并确定了他们的白血病细胞来源。cll衍生的ev能够诱导CART细胞功能障碍状态，其特征是表型、功能和转录的衰竭变化。我们证明，具体来说，PD-L1(+) cll衍生的ev诱导CART细胞衰竭。总之，我们确定了CLL患者的ev诱导CART细胞衰竭的重要机制。
Chimeric antigen receptor (CAR) T cell therapy has yielded unprecedented outcomes in some patients with hematological malignancies; however, inhibition by the tumor microenvironment has prevented the broader success of CART cell therapy. We used chronic lymphocytic leukemia (CLL) as a model to investigate the interactions between the tumor microenvironment and CART cells. CLL is characterized by an immunosuppressive microenvironment, an abundance of systemic extracellular vesicles (EVs), and a relatively lower durable response rate to CART cell therapy. In this study, we characterized plasma EVs from untreated CLL patients and identified their leukemic cell origin. CLL-derived EVs were able to induce a state of CART cell dysfunction characterized by phenotypical, functional, and transcriptional changes of exhaustion. We demonstrate that, specifically, PD-L1(+) CLL-derived EVs induce CART cell exhaustion. In conclusion, we identify an important mechanism of CART cell exhaustion induced by EVs from CLL patients.