2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
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2B4共刺激结构域增强抗CD5嵌合抗原受体工程自然杀伤细胞对抗T细胞恶性肿瘤的细胞毒能力
DOI：
10.1186/s13045-019-0732-7
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发表时间：
2019-05-16
影响因子：
28.5
通讯作者：
Wang，Jianxiang
中科院分区：
文献类型：
--
作者：
Xu，Yingxi;Liu，Qian;Wang，Jianxiang
背景嵌合抗原受体工程化T细胞（CAR-T）在B细胞恶性肿瘤治疗中表现出非凡的疗效，并已被美国食品药品监督管理局批准用于弥漫性大B细胞淋巴瘤和急性B淋巴细胞白血病的治疗。然而，由于恶性T细胞和正常T细胞之间共有的抗原，使用CAR-T细胞治疗T细胞恶性肿瘤仍然有限。CD 5被认为是恶性T细胞的重要特征性标志物之一，并且在几乎所有正常T细胞上表达，但在NK-92细胞上不表达。最近，NK-92细胞已被用作CAR修饰的免疫细胞。然而，在临床前模型中，CAR-T细胞似乎上级CAR-NK-92细胞。因此，我们推测，除了小鼠NK-92细胞寿命短之外，CAR构建体中使用的共刺激结构域可能不适合CAR-NK-92细胞工程。一种使用T细胞相关活化受体-4-1BB（BB.z），另一种使用NK细胞相关活化受体-2B4（2B4.z）。随后，产生BB.z-NK和2B 4.z-NK。体外评价了对CD 5+恶性细胞系、原代CD 5+恶性细胞和正常T细胞的特异性细胞毒性。结果BB.z-NK和2B 4.z-NK在体外对CD 5 +T细胞急性淋巴细胞白血病（T-ALL）小鼠具有特异性杀伤作用，并能延长T-ALL移植瘤小鼠的生存期。2B 4.z-NK细胞具有更强的抗CD 5+恶性肿瘤的能力，同时也具有更强的直接溶解性副作用。结论抗CD 5 CAR-NK细胞，尤其是含有NK细胞相关活化受体2B 4胞内结构域的CAR-NK细胞，可能成为治疗T细胞恶性肿瘤的一种有前景的策略。
BackgroundChimeric antigen receptor engineered T cells (CAR-T) have demonstrated extraordinary efficacy in B cell malignancy therapy and have been approved by the US Food and Drug Administration for diffuse large B cell lymphoma and acute B lymphocytic leukemia treatment. However, treatment of T cell malignancies using CAR-T cells remains limited due to the shared antigens between malignant T cells and normal T cells. CD5 is considered one of the important characteristic markers of malignant T cells and is expressed on almost all normal T cells but not on NK-92 cells. Recently, NK-92 cells have been utilized as CAR-modified immune cells. However, in preclinical models, CAR-T cells seem to be superior to CAR-NK-92 cells. Therefore, we speculate that in addition to the short lifespan of NK-92 cells in mice, the costimulatory domain used in CAR constructs might not be suitable for CAR-NK-92 cell engineering.MethodsTwo second-generation anti-CD5 CAR plasmids with different costimulatory domains were constructed, one using the T-cell-associated activating receptor-4-1BB (BB.z) and the other using a NK-cell-associated activating receptor-2B4 (2B4.z). Subsequently, BB.z-NK and 2B4.z-NK were generated. Specific cytotoxicity against CD5+malignant cell lines, primary CD5+malignant cells, and normal T cells was evaluated in vitro. Moreover, a CD5+T cell acute lymphoblastic leukemia (T-ALL) mouse model was established and used to assess the efficacy of CD5-CAR NK immunotherapy in vivo.ResultsBoth BB.z-NK and 2B4.z-NK exhibited specific cytotoxicity against CD5+malignant cells in vitro and prolonged the survival of T-ALL xenograft mice. Encouragingly, 2B4.z-NK cells displayed greater anti-CD5+malignancy capacity than that of BB.z-NK, accompanied by a greater direct lytic side effect versus BB.z-NK.ConclusionsAnti-CD5 CAR-NK cells, particularly those constructed with the intracellular domain of NK-cell-associated activating receptor 2B4, may be a promising strategy for T cell malignancy treatment.