Activated Monocytes in Peritumoral Stroma of Hepatocellular Carcinoma Promote Expansion of Memory T Helper 17 Cells
Activated Monocytes in Peritumoral Stroma of Hepatocellular Carcinoma Promote Expansion of Memory T Helper 17 Cells
复制标题
肝细胞癌瘤周基质中活化的单核细胞促进记忆辅助T 17细胞的扩增
DOI：
10.1002/hep.23291
复制
发表时间：
2010-01-01
期刊：
影响因子：
13.5
通讯作者：
Zheng, Limin
中科院分区：
文献类型：
--
作者：
Kuang, Dong-Ming;Peng, Chen;Zheng, Limin
尽管癌症患者表现出全身性免疫抑制状态，但大量证据表明，肿瘤部位的炎症反应可以促进肿瘤的生长和进展。肝细胞癌（HCC）通常起源于炎症性肝硬化，伴广泛的白细胞浸润。我们最近发现促炎T辅助（Th）17细胞在HCC组织中积累，它们通过促进血管生成来促进疾病进展。本研究表明，产生白细胞介素(IL) - 17 -的细胞主要富集于HCC组织的瘤周基质中，其水平与同一区域的单核细胞/巨噬细胞密度密切相关。大多数瘤周CD68+细胞表现为活化表型。因此，在体外循环记忆T细胞诱导Th17细胞扩增方面，肿瘤活化单核细胞明显优于抑制性肿瘤巨噬细胞，其表型特征与从hcc分离的细胞相似。此外，我们发现肿瘤激活的单核细胞分泌一组关键的促炎细胞因子，可触发功能性Th17细胞的增殖。抑制肝脏单核/巨噬细胞炎症可显著降低肿瘤浸润Th17细胞水平和体内肿瘤生长。结论：促炎Th17细胞在不同的HCC微环境中由不同类型的免疫细胞之间的精细协同作用产生和调节，并允许激活的单核细胞的炎症反应向促肿瘤方向改变。选择性调节肿瘤中炎症反应的“环境”可能为抗癌治疗提供一种新的策略。(肝脏病学2009。)
Although cancer patients exhibit a generalized immunosuppressive status, substantial evidence indicates that the inflammatory reaction at a tumor site can promote tumor growth and progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with extensive leukocyte infiltration. We recently found that proinflammatory T helper (Th)17 cells are accumulated in HCC tissue, where they promote disease progression by fostering angiogenesis. Here we show that interleukin (IL)‐17‐producing cells were enriched predominantly in peritumoral stroma of HCC tissues, and their levels were well correlated with monocyte/macrophage density in the same area. Most peritumoral CD68+ cells exhibited an activated phenotype. Accordingly, tumor‐activated monocytes were significantly superior to the suppressive tumor macrophages in inducing expansion of Th17 cells from circulating memory T cells in vitro with phenotypic features similar to those isolated from HCCs. Moreover, we found that tumor‐activated monocytes secreted a set of key proinflammatory cytokines that triggered proliferation of functional Th17 cells. Inhibition of monocytes/macrophages inflammation in liver markedly reduced the level of tumor‐infiltrating Th17 cells and tumor growth in vivo. Conclusion: The proinflammatory Th17 cells are generated and regulated by a fine‐tuned collaborative action between different types of immune cells in distinct HCC microenvironments, and allows the inflammatory response of activated monocytes to be rerouted in a tumor‐promoting direction. Selectively modulating the “context” of inflammatory response in tumors might provide a novel strategy for anticancer therapy. (HEPATOLOGY 2009.)