NKG2D-CAR 记忆 T 细胞在体外和体内针对儿童 T 细胞急性淋巴细胞白血病，但无法消除白血病起始细胞。
NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and in vivo but fail to eliminate leukemia initiating cells.
发表日期：2023
作者：
Marta Ibáñez-Navarro, Adrián Fernández, Adela Escudero, Gloria Esteso, Carmen Campos-Silva, Miguel Ángel Navarro-Aguadero, Alejandra Leivas, Beatriz Ruz Caracuel, Carlos Rodríguez-Antolín, Alejandra Ortiz, Alfonso Navarro-Zapata, Carmen Mestre-Durán, Manuel Izquierdo, María Balaguer-Pérez, Cristina Ferreras, Joaquín Martínez-López, Mar Valés-Gómez, Antonio Pérez-Martínez, Lucía Fernández
来源：
Experimental Hematology & Oncology
摘要：
难治性/复发性儿童急性白血病在临床上仍然具有挑战性，需要新的治疗策略。在细胞毒性免疫细胞中表达的自然杀伤组 2D (NKG2D) 受体与其配体 (NKG2DL) 之间的相互作用对于抗白血病免疫监视非常重要，NKG2DL 在白血病细胞中表达上调。然而，白血病细胞可能会发展出NKG2DL脱落和/或下调等免疫逃逸策略。在本报告中，我们分析了NKG2D嵌合抗原受体（CAR）重定向记忆（CD45RA-）T细胞的体外和小鼠模型中的抗白血病活性T 细胞急性淋巴细胞白血病 (T-ALL)。我们还在体外探索了可溶性NKG2DL（sNKG2DL）如何影响NKG2D-CAR T细胞的细胞毒性以及NKG2D-CAR T细胞对Jurkat细胞基因表达和体内功能的影响。在体外，我们发现NKG2D-CAR T细胞靶向白血病细胞并表现出对 sNKG2DL 所产生的免疫抑制作用的抵抗力。在体内，NKG2D-CAR T 细胞控制了 T 细胞白血病负担并提高了治疗小鼠的存活率，但未能治愈动物。经过 CAR T 细胞治疗后，Jurkat 细胞上调与增殖、存活和干性相关的基因，并且在体内，它们表现出白血病起始细胞的功能特性。此处提供的数据表明，与其他治疗方法相结合，NKG2D-CAR T细胞可能是儿科 T-ALL 的一种新型治疗方法。版权所有 © 2023 Ibáñez-Navarro、Fernández、Escudero、Esteso、Campos-Silva、Navarro-Aguadero、Leivas、Caracuel、Rodríguez-Antolín、Ortiz、Navarro-Zapata、Mestre-Durán 、伊斯基耶多、巴拉格尔-佩雷斯、费雷拉斯、马丁内斯-洛佩斯、瓦莱斯-戈麦斯、佩雷斯-马丁内斯和费尔南德斯。
Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation.In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells' cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality.In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells.The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.Copyright © 2023 Ibáñez-Navarro, Fernández, Escudero, Esteso, Campos-Silva, Navarro-Aguadero, Leivas, Caracuel, Rodríguez-Antolín, Ortiz, Navarro-Zapata, Mestre-Durán, Izquierdo, Balaguer-Pérez, Ferreras, Martínez-López, Valés-Gómez, Pérez-Martínez and Fernández.