细胞毒性T细胞
旁观者效应
CD28
T细胞
细胞疗法
CD8型
人口
白细胞介素21
免疫学
CCL5
医学
癌症研究
生物
细胞生物学
白细胞介素2受体
干细胞
免疫系统
体外
生物化学
环境卫生
作者
James J. Kaminski,Ryan A Fleming,Francesca Alvarez-Calderon,Marlana B Winschel,Connor McGuckin,Eric K. Ho,Fay Eng,Xianliang Rui,Paula Keskula,Lorenzo Cagnin,Joanne Charles,Jillian Zavistaski,Steven Margossian,Malika Kapadia,James B. Rottman,Jennifer Lane,Susanne H.C. Baumeister,Victor Tkachev,Alex K. Shalek,Leslie S. Kean,Ulrike Gerdemann
出处
期刊:Blood
[American Society of Hematology]
日期:2024-04-01
标识
DOI:10.1182/blood.2023022717
摘要
CAR-T cells hold promise as a therapy for B-cell-derived malignancies, yet despite their impressive initial response rates, a significant proportion of patients ultimately experience relapse. While recent studies have explored the mechanisms of in vivo CAR-T cell function, little is understood about the activation of surrounding CARneg bystander T-cells and their potential to enhance tumor responses. We performed single-cell RNA-Seq (scRNA-Seq) on non-human primate (NHP) and patient-derived T-cells to identify the phenotypic and transcriptomic hallmarks of bystander activation of CARneg T-cells following B-cell targeted CAR-T cell therapy. Utilizing a highly translatable CD20 CAR NHP model, we observed a distinct population of activated CD8+ CARneg T-cells emerging during CAR-T cell expansion. These bystander CD8+ CARneg T-cells exhibited a unique transcriptional signature with upregulation of NK-cell markers (KIR3DL2, CD160, KLRD1), chemokines and chemokine receptors (CCL5, XCL1, CCR9), and downregulation of naive T-cell-associated genes (SELL, CD28). A transcriptionally similar population was identified in patients following Tisagenlecleucel infusion. Mechanistic studies revealed that IL-2 and IL-15 exposure induced bystander-like CD8+ T-cells in a dose dependent manner. In vitro activated and patient-derived T-cells with the bystander phenotype efficiently killed leukemic cells through a TCR-independent mechanism. Collectively, this dataset provides the first comprehensive identification and profiling of CARneg bystander CD8+ T-cells following B-cell targeting CAR-T cell therapy and suggests a novel mechanism through which CAR-T cell infusion might trigger enhanced anti-leukemic responses.
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