Arming Cytokine-induced Killer Cells With Chimeric Antigen Receptors: CD28 Outperforms Combined CD28 OX40 "Super-stimulation"
Arming Cytokine-induced Killer Cells With Chimeric Antigen Receptors: CD28 Outperforms Combined CD28 OX40 "Super-stimulation"
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DOI：
10.1038/mt.2013.192
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发表时间：
2013-12-01
影响因子：
12.4
通讯作者：
Abken, Hinrich
中科院分区：
文献类型：
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作者：
Hombach, Andreas A.;Rappl, Gunter;Abken, Hinrich
细胞因子诱导的杀伤（CIK）细胞由于其以HLA非依赖性方式识别和破坏自体肿瘤细胞的能力而引起了人们对用于细胞抗肿瘤治疗的兴趣。CIK细胞主要由终末分化的CD 8（+）CD 56（+）细胞组成，其抗肿瘤攻击可以通过识别肿瘤细胞并触发CIK细胞活化的嵌合抗原受体（CAR）重定向来改善。然而，CIK细胞活化的要求迄今为止较少探索，并且可能与“年轻”T细胞的要求不同。我们揭示，与第一代zeta-CAR相比，CD 28和0X 40汽车产生更高的干扰素分泌;然而，CD 28-zeta和第三代CD 28-zeta-0X 40 CAR在调节大多数CIK细胞效应子功能方面表现相似。然而，与CD 28-zeta CAR相比，CD 28-zeta-OX 40 CAR加速了CD 56（+）CIK细胞的终末成熟，产生高频率的活化诱导细胞死亡（AICD），并降低了体内抗肿瘤效率。因此，CD 56（-）表型的CD 28-zeta CAR CIK细胞在重定向肿瘤细胞消除中具有上级优势。CAR介导的CIK细胞活化也增加了抗原非依赖性靶细胞裂解; CD 28-zeta CAR比CD 28-zeta-OX 40 CAR更有效。转化为治疗策略，CAR重定向的CIK细胞受益于CD 28共刺激;然而，由于增加的AICD，CD 28-zeta-OX 40 CAR的“超共刺激”在抗肿瘤功效方面表现较低。
Cytokine-induced killer (CIK) cells raised interest for use in cellular antitumor therapy due to their capability to recognize and destroy autologous tumor cells in a HLA-independent fashion. The antitumor attack of CIK cells, predominantly consisting of terminally differentiated CD8(+)CD56(+) cells, can be improved by redirecting by a chimeric antigen receptor (CAR) that recognizes the tumor cell and triggers CIK cell activation. The requirements for CIK cell activation were, however, so far less explored and are likely to be different from those of "younger" T cells. We revealed that CD28 and OX40 CARs produced higher interferon- secretion as compared with the first-generation zeta-CAR; CD28-zeta and the third-generation CD28-zeta-OX40 CAR, however, performed similar in modulating most CIK cell effector functions. Compared with the CD28-zeta CAR, however, the CD28-zeta-OX40 CAR accelerated terminal maturation of CD56(+) CIK cells producing high frequencies in activation-induced cell death (AICD) and reduced antitumor efficiency in vivo. Consequently, CD28-zeta CAR CIK cells of CD56(-) phenotype were superior in redirected tumor cell elimination. CAR-mediated CIK cell activation also increased antigen-independent target cell lysis; the CD28-zeta CAR was more efficient than the CD28-zeta-OX40 CAR. Translated into therapeutic strategies, CAR-redirected CIK cells benefit from CD28 costimulation; "super-costimulation" by the CD28-zeta-OX40 CAR, however, performed less in antitumor efficacy due to increased AICD.