Distinct responses of two hepatocellular carcinoma cell lines of a similar origin to immunotherapies targeting regulatory or effector T cells

效应T细胞（Teff）和调节性T细胞（Treg）之间的平衡似乎对有效的抗肿瘤免疫治疗非常关键。在两种相似来源的小鼠肝癌细胞系MH129和MH134之间比较Teff增强和Treg抑制的治疗效果。通过用表达糖皮质激素诱导的肿瘤坏死因子受体相关蛋白（GITR）的腺病毒感染肿瘤细胞来增强Teff，并通过施用抗CD25单克隆抗体（PC 61）或低剂量环磷酰胺来消耗CD4+CD25+天然存在的Treg来抑制Treg。我们的数据表明，MH129细胞对Treg耗竭敏感，但对GITR表达具有抗性，MH134细胞反之亦然。因此，在MH129细胞中，在肿瘤细胞接种之前或之后分别完全或部分地注射PC 61根除了肿瘤生长。肿瘤细胞接种后给予低剂量环磷酰胺也可延缓肿瘤生长。 关于我们 然而，无论是在体外还是在体内，GTTR表达几乎没有表现出效果。相比之下，在MH134细胞中，仅当在肿瘤细胞接种之前注射时，PC 61诱导部分肿瘤生长延迟，并且低剂量环磷酰胺没有显示出效果，但是GTTR，特别是当在体外施用时，抑制肿瘤生长。仅在MH134细胞中观察到PC61和GITR的累加效应。在两种肿瘤模型的实验过程中，外周血CD4+CD25+ CD4+ T细胞的比例保持不变。根据这些结果，我们推测这种不同的灵敏度可能是由于Teff相对于Treg的相对诱导水平的差异，而不是由于两种肿瘤模型之间外周Treg的不同免疫原性或不同动力学。鉴定这些肿瘤细胞系中Teff和Treg特异性的抗原或表位的未来研究是必要的，因为对此类抗原或表位的免疫应答的分析通常可以帮助预测不同免疫疗法针对不同肿瘤的相对功效。少

Balance between effector T cells (Teff)and regulatory T cells (Treg)appears to be very crucial for effective anti-tumor immunotherapy. The therapeutic efficacies of enhancement of Teff and suppression of Treg were compared between two murine hepatoma cell lines of a similar origin, MH129 and MH134. Enhancement of Teff was achieved by infection of tumor cells with adenovirus expressing glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), and suppression of Treg, by depletion of CD4+CD25+ naturally occurring Treg by administration of anti-CD25 monoclonal antibody (PC61)or low-dose cyclophosphamide. Our data show that MH129 cells were susceptible to Treg depletion but resistant to GITR expression, and vice versa for MH134 cells. Thus, in MH129 cells, injection of PC61 prior to or after tumor cell inoculation completely or partially, respectively, eradicated tumor growth. Low-dose cyclophosphamide administered after tumor cell inoculation also delayed tumor growth. … More However, GTTR expression either in vitroor in vivo exhibited little effect. In contrast, in MH134 cells, PC61 induced partial tumor growth delay only when injected prior to tumor cell inoculation, and low-dose cyclophosphamide showed no effect, but GTTR, particularly when administered in vitro, inhibited tumor growth. An additive effect of PC61 and GITR was observed only in MH134 cells. The ratios of peripheral CD4+CD25+ CD4+ T cells remained unaltered during the experimental course in both tumor models. From these results we speculate that this different sensitivity may be due to a difference in relative induction levels of Teff versus Treg, not due to different immunogenicity or different kinetics of peripheral Treg, between the two tumor models. Future studies identifying antigen (s) or epitope (s) specific for Teff and Treg in these tumor cell lines are necessary as analysis of the immune response to such antigen (s) or epitope (s) may in general help predict the relative efficacy of different immunotherapies against distinct tumors. Less