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

我们在过去已经证明，“CTLA-4”是一个对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。在本项目中，我们推断其在Treg细胞上的表达也可能促进肿瘤组织中抗原呈递细胞（antigen-presenting cells, APCs）的负变化。首先，我们评估了CTLA-4的表达水平，发现与其他组织中的Treg细胞相比，肿瘤中的Treg细胞表面有大量的CTLA-4。由于CTLA-4会对抗原提呈细胞的外观和功能产生负面影响，所以我们也检查了这些细胞在Treg细胞高和低的肿瘤中是否存在差异。高Treg细胞肿瘤内的抗原呈递细胞表达较低水平的某些共刺激分子与小鼠相比，大量减少Treg部分引起的消耗。与来自缺乏Treg细胞的肿瘤的apc相比，来自高Treg细胞的肿瘤的apc启动T细胞反应的能力较差，支持这一观察结果。最后，我们在组织培养中检测肿瘤Treg细胞是否能诱导T细胞出现异常。事实上，肿瘤Treg细胞促进了与Treg细胞一起培养的T细胞表面一些与功能受损相关的蛋白质的表达增加。总的来说，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，能够破坏肿瘤中Treg功能的疗法应该有望治疗癌症。

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.