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

两种来源相似的肝细胞癌细胞系对针对调节性 T 细胞或效应 T 细胞的免疫疗法的不同反应

• 批准号: 18590739
• 负责人: NAKAO Kazuhiko
• 金额: $ 2.42万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590739/
• 关键词: regulatory T cells(Treg); effector T cells(Teff); hepatoma; PC61; cyclophosphamide; GITRL

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

效应性T细胞和调节性T细胞之间的平衡对于有效的抗肿瘤免疫治疗至关重要。本文比较了两种来源相似的小鼠肝癌细胞系MH129和MH134对TJeff的增强和对Treg的抑制作用。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，用抗CD25单抗(PC61)或小剂量环磷酰胺去除自然产生的CD25+Treg，抑制Treg。我们的数据显示，MH129细胞对Treg耗竭敏感，但对GITR表达耐药，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注射PC61分别完全或部分地根除了肿瘤的生长。在肿瘤细胞接种后给予小剂量环磷酰胺也可以延缓肿瘤生长。…然而，无论是在体外还是在体内，GTTR的表达都没有显示出什么影响。相反，在MH134细胞中，PC61仅在肿瘤细胞接种前注射时才诱导部分肿瘤生长延迟，小剂量环磷酰胺没有任何作用，但GTTR，特别是在体外给药时，抑制了肿瘤的生长。PC61和GITR只有在MH134细胞中有相加作用。在两种肿瘤模型的实验过程中，外周血中CD4+CD25+CD4+T细胞的比例保持不变。根据这些结果，我们推测，这种不同的敏感性可能是由于两种肿瘤模型中TREF和Treg的相对诱导水平不同，而不是由于免疫原性或外周Treg动力学的不同。未来有必要在这些肿瘤细胞系中识别针对Tef和Treg的抗原(S)或表位(S)，因为对这些抗原(S)或表位(S)的免疫反应分析通常有助于预测不同免疫疗法对不同肿瘤的相对疗效。较少

项目成果

Abrogation of constitutive STAT3 activity sensitzes human hepatoma cells to TRAIL-mediated apoptosis

STAT3 组成型活性的消除使人肝癌细胞对 TRAIL 介导的细胞凋亡敏感

• 发表时间: 2007
• 期刊: Journal of Hepatology 47・4
• 作者: Kusaba Mariko;et. al.
• 通讯作者: et. al.

DHMEQ,a novel NF-κB inhibitor,induces apoptosis and cell-cycle arrest in human hepatoma cells

DHMEQ 是一种新型 NF-κB 抑制剂，可诱导人肝癌细胞凋亡和细胞周期停滞

• 发表时间: 2006
• 期刊: Ihternational Joumal of Oncology 29・3
• 作者: Nishimura Daisuke;et. al.
• 通讯作者: et. al.

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

两种来源相似的肝细胞癌细胞系对针对调节性 T 细胞或效应 T 细胞的免疫疗法的不同反应

• 发表时间: 2007
• 期刊: Oncology Repoets 17・5
• 作者: Nagayama Yuji;et. al.
• 通讯作者: et. al.

Association between liver fibrosis and insulin sensitivity in chronic hepatitis c patients

• DOI: 10.1111/j.1572-0241.2006.00835.x
• 发表时间: 2006-12-01
• 期刊: AMERICAN JOURNAL OF GASTROENTEROLOGY
• 影响因子: 9.8
• 作者: Taura, Naota;Ichikawa, Tatsuki;Eguchi, Katsumi
• 通讯作者: Eguchi, Katsumi

Abrogation of constitutive STAT3 activity sensitizes human hepatoma cells to TRAIL-mediated apoptosis

• DOI: 10.1016/j.jhep.2007.04.017
• 发表时间: 2007-10-01
• 期刊: JOURNAL OF HEPATOLOGY
• 影响因子: 25.7
• 作者: Kusaba, Mariko;Nakao, Kazuhiko;Eguchi, Katsumi
• 通讯作者: Eguchi, Katsumi