制御性Ｔ細胞による腫瘍内ＣＤ８＋Ｔ細胞の活性抑制に関する研究

调节性T细胞抑制瘤内CD8+T细胞活性的研究

• 批准号: 12F02423
• 负责人: 坂口 志文
• 金额: $ 1.47万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12F02423/
• 关键词: Regulatory T cell; Cancer; Immunotherapy; CD8; Exhaustion; Drug; Dysfunction; Protein; T細胞

We have demonstrated in the past that “CTLA-4” is a molecule that is critical for Treg function especially in the context of autoimmune disease. In this project, we reasoned that its expression on Treg cells may also promote negative changes antigen-presenting cells (APCs) in the tumor tissue. First, we evaluated the expression levels of CTLA-4 and found that compared to the Tregs in other tissues, the Treg cells in the tumor have substantially higher amount of CTLA-4 on their surface. Since CTLA-4 can negatively affect the appearance and function of antigen-presenting cells, we also checked whether there are differences in these cells in tumors with high or low Treg cells. Antigen-presenting cells within tumors with high Treg cells expressed lower levels certain costimulatory molecules compared to mice with much reduced Treg fractions arising from depletion. In support of this observation, APCs from the tumors with high Treg cells showed poor ability to initiate T cell response compared to APCs from tumors lacking Treg cells.Lastly, we checked whether Treg cells from tumors can induce an abnormal appearance on T cells when tested in tissue culture. Indeed, tumor-Treg cells promoted increased expression of a number of proteins associated with impaired function on the surface of T cells that were cultured with the Treg cells.Overall, our findings provide potential explanation for how Treg cells may promote T cell dysfunction in the tumor. Thus, therapies that can disrupt Treg function in the tumor should hold promise for treating cancer.

我们在过去已经证明，“CTLA-4”是一种对Treg功能至关重要的分子，特别是在自身免疫性疾病的背景下。在这个项目中，我们推测它在Treg细胞上的表达也可能促进肿瘤组织中的抗原提呈细胞(APC)的阴性变化。首先，我们评估了CTLA-4的表达水平，发现与其他组织中的Tregs相比，肿瘤中的Treg细胞表面的CTLA-4含量要高得多。由于CTLA-4可以对抗原提呈细胞的外观和功能产生负面影响，我们还检查了在Treg细胞高或低的肿瘤中，这些细胞是否存在差异。高Treg细胞的肿瘤内的抗原提呈细胞表达较低水平的某些共刺激分子，而小鼠因耗竭而产生的Treg组分大大减少。为了支持这一观察结果，来自高Treg细胞肿瘤的APC与来自没有Treg细胞的肿瘤的APC相比，启动T细胞反应的能力较差。最后，我们检查了来自肿瘤的Treg细胞在组织培养中是否能够诱导T细胞的异常出现。事实上，肿瘤-Treg细胞促进了与Treg细胞培养的T细胞表面与功能受损相关的一些蛋白质的表达增加。综上所述，我们的发现为Treg细胞如何促进肿瘤中T细胞功能障碍提供了潜在的解释。因此，可以破坏肿瘤中Treg功能的治疗方法应该有望用于癌症的治疗。