Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA.
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
Mol Ther. 2020 Dec 2;28(12):2577-2592. doi: 10.1016/j.ymthe.2020.07.023. Epub 2020 Jul 25.
T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have produced impressive outcomes for the treatment of B cell malignancies, but different products vary in kinetics, persistence, and toxicity profiles based on the co-stimulatory domains included in the CAR. In this study, we performed transcriptional profiling of bulk CAR T cell populations and single cells to characterize the transcriptional states of human T cells transduced with CD3ζ, 4-1BB-CD3ζ (BBζ), or CD28-CD3ζ (28ζ) co-stimulatory domains at rest and after activation by triggering their CAR or their endogenous T cell receptor (TCR). We identified a transcriptional signature common across CARs with the CD3ζ signaling domain, as well as a distinct program associated with the 4-1BB co-stimulatory domain at rest and after activation. CAR T cells bearing BBζ had increased expression of human leukocyte antigen (HLA) class II genes, ENPP2, and interleukin (IL)-21 axis genes, and decreased PD1 compared to 28ζ CAR T cells. Similar to previous studies, we also found BBζ CAR CD8 T cells to be enriched in a central memory cell phenotype and fatty acid metabolism genes. Our data uncovered transcriptional signatures related to costimulatory domains and demonstrated that signaling domains included in CARs uniquely shape the transcriptional programs of T cells.
经嵌合抗原受体（CAR）修饰表达靶向 CD19 的 T 细胞在治疗 B 细胞恶性肿瘤方面取得了令人瞩目的疗效，但不同产品的动力学、持久性和毒性特征因 CAR 中包含的共刺激结构域而异。在这项研究中，我们对 CAR T 细胞群体的转录组进行了分析，并对单细胞进行了分析，以表征用 CD3ζ、4-1BB-CD3ζ（BBζ）或 CD28-CD3ζ（28ζ）共刺激结构域转导的人 T 细胞在静息状态和通过触发其 CAR 或内源性 T 细胞受体（TCR）激活后的转录状态。我们鉴定了一种与 CD3ζ 信号结构域相关的跨 CAR 共同转录特征，以及一种与 4-1BB 共刺激结构域在静息和激活时相关的独特程序。与 28ζ CAR T 细胞相比，携带 BBζ 的 CAR T 细胞表达更高的人类白细胞抗原（HLA）II 类基因、ENPP2 和白细胞介素（IL）-21 轴基因，并且 PD1 表达降低。与之前的研究类似，我们还发现 BBζ CAR CD8 T 细胞富含中央记忆细胞表型和脂肪酸代谢基因。我们的数据揭示了与共刺激结构域相关的转录特征，并表明 CAR 中包含的信号结构域独特地塑造了 T 细胞的转录程序。
