Tumor-Activated Monocytes Promote Expansion of IL-17-Producing CD8+ T Cells in Hepatocellular Carcinoma Patients
Tumor-Activated Monocytes Promote Expansion of IL-17-Producing CD8+ T Cells in Hepatocellular Carcinoma Patients
复制标题
DOI：
10.4049/jimmunol.0904094
复制
发表时间：
2010-08-01
影响因子：
4.4
通讯作者：
Zheng, Limin
中科院分区：
文献类型：
--
作者：
Kuang, Dong-Ming;Peng, Chen;Zheng, Limin
最近在肿瘤中发现了产生IL-17的前炎性CD8(+)T细胞(Tc17细胞)，但这些细胞在人类肿瘤中的性质和调节目前尚不清楚。我们最近发现IL-17(+)细胞聚集在人肝细胞癌中，它们通过促进血管生成来促进疾病的进展。在这项研究中，我们发现在人肝细胞癌中，Tc17细胞构成了产生IL-17的细胞的显著部分。虽然大多数循环中的Tc17细胞都不表达干扰素-γ，但80%的肝癌组织中的Tc17细胞表达干扰素-γ，并且主要集中在肿瘤侵袭的边缘。大多数位于肿瘤侵袭边缘的CD68(+)细胞表现为活化的表型，相应地，从肝癌组织分离的活化单核细胞在体外诱导Tc17细胞的扩增方面明显优于从非肿瘤组织分离的单核细胞，其表型特征与从肿瘤分离的单核细胞相似。与IL-17(-)干扰素-γ(+)CD8(+)细胞相比，这些干扰素-γ(+)Tc17细胞具有更高的促炎细胞因子(IL-2、IL-22和TNF-α)的表达，而颗粒酶B和穿孔素的表达则显著降低。此外，我们还发现，肿瘤激活的单核细胞分泌一系列关键的细胞因子(IL-1β、IL-6和IL-23)来触发Tc17细胞的增殖。这些数据揭示了一种有趣的机制，在这种机制中，人类Tc17细胞是由不同类型的免疫细胞在不同的肿瘤微环境中微调的协同作用产生的。《免疫学杂志》，2010,185：1544-1549。
The proinflammatory IL-17-producing CD8(+) T cells (Tc17 cells) have recently been detected in tumors, but the nature and regulation of these cells in human tumors are presently unknown. We have recently found that IL-17(+) cells are accumulated in human hepatocellular carcinomas (HCC), where they promote disease progression by fostering angiogenesis. In this study, we showed that Tc17 cells constitute a remarkable portion of IL-17-producing cells in human HCC. Although most circulating Tc17 cells were negative for IFN-gamma, >80% of Tc17 cells in HCC tissues were positive for IFN-g, and they were enriched predominantly in invading tumor edge. Most CD68(+) cells located in invading tumor edge exhibited an activated phenotype and, accordingly, the activated monocytes isolated from HCC tissues were significantly superior to those isolated from nontumor tissues in inducing expansion of Tc17 cells in vitro with phenotypic features similar to those isolated from tumors. Compared with IL-17(-)IFN-gamma(+) CD8(+) cells, these IFN-gamma(+) Tc17 cells have significantly higher expression of proinflammatory cytokines (IL-2, IL-22, and TNF-alpha), but reduced expression of granzyme B and perforin. Moreover, we found that tumor-activated monocytes secreted a set of key cytokines (IL-1 beta, IL-6, and IL-23) to trigger the proliferation of Tc17 cells. These data reveal an intriguing mechanism in which human Tc17 cells are generated by a fine-tuned collaborative action between different types of immune cells in distinct tumor microenvironments. The Journal of Immunology, 2010, 185: 1544-1549.