Ye Zhenmin, Tang Chaoke, Xu Shulin, Zhang Bei, Zhang Xueshu, Moyana Terence, Yang Jicheng, Xiang Jim
Research Unit, Saskatchewan Cancer Agency, Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 4H4, Canada.
Cell Mol Immunol. 2007 Aug;4(4):277-85.
CD8+ cytotoxic T (Tc) cells play a crucial role in host immune responses to cancer, and in this context, adoptive CD8+ Tc cell therapy has been studied in numerous animal tumor models. Its antitumor efficacy is, to a large extent, determined by the ability of Tc cells to survive and infiltrate tumors. In clinical trials, such in vitro-activated T cells often die within hours to days, and this greatly limits their therapeutic efficacy. CD8+ Tc cells fall into two subpopulations based upon their differential cytokine secretion. In this study, we in vitro generated that ovalbumin (OVA)-pulsed dendritic cell (DCOVA)-activated CD8+ type 1 Tc (Tc1) cells secreting IFN-gamma, and CD8+ type 2 Tc (Tc2) cells secreting IL-4, IL-5 and IL-10, which were derived from OVA-specific T cell receptor (TCR) transgenic OT I mice. We then systemically investigated the in vitro and in vivo effector function and survival of Tc1 and Tc2 cells, and then assessed their survival kinetics after adoptively transferred into C57BL/6 mice, respectively. We demonstrated that, when compared to CD8+ Tc2, Tc1 cells were significantly more effective in perforin-mediated cytotoxicity to tumor cells, had a significantly higher capacity for in vivo survival after the adoptive T cell transfer, and had a significantly stronger therapeutic effect on eradication of well-established tumors expressing OVA in animal models. In addition, CD8+ Tc1 and Tc2 cells skewed the phenotype of CD4+ T cells toward Th1 and Th2 type, respectively. Therefore, the information regarding the differential effector function, survival and immune modulation of CD8+ Tc1 and Tc2 cells may provide useful information when preparing in vitro DC-activated CD8+ T cells for adoptive T cell therapy of cancer.
CD8 + 细胞毒性T(Tc)细胞在宿主对癌症的免疫反应中起关键作用,在此背景下,已在众多动物肿瘤模型中研究了过继性CD8 + Tc细胞疗法。其抗肿瘤功效在很大程度上取决于Tc细胞存活和浸润肿瘤的能力。在临床试验中,这种体外激活的T细胞通常在数小时至数天内死亡,这极大地限制了它们的治疗效果。CD8 + Tc细胞根据其不同的细胞因子分泌可分为两个亚群。在本研究中,我们在体外产生了分泌干扰素-γ的卵清蛋白(OVA)脉冲树突状细胞(DCOVA)激活的CD8 + 1型Tc(Tc1)细胞,以及分泌白细胞介素-4、白细胞介素-5和白细胞介素-10的CD8 + 2型Tc(Tc2)细胞,这些细胞来源于OVA特异性T细胞受体(TCR)转基因OT I小鼠。然后,我们系统地研究了Tc1和Tc2细胞的体外和体内效应功能及存活情况,并分别评估了它们过继转移到C57BL / 6小鼠后的存活动力学。我们证明,与CD8 + Tc2相比,Tc1细胞在穿孔素介导的对肿瘤细胞的细胞毒性方面显著更有效,在过继性T细胞转移后体内存活能力显著更高,并且在动物模型中对根除表达OVA的已建立肿瘤具有显著更强的治疗效果。此外,CD8 + Tc1和Tc2细胞分别使CD4 + T细胞的表型向Th1和Th2型倾斜。因此,关于CD8 + Tc1和Tc2细胞不同效应功能、存活和免疫调节的信息,在为癌症的过继性T细胞疗法制备体外DC激活的CD8 + T细胞时可能提供有用的信息。