Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer
Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer
复制标题
DOI：
10.1073/pnas.0710686105
复制
发表时间：
2008-10-07
影响因子：
11.1
通讯作者：
Wang, Rong-Fu
中科院分区：
文献类型：
--
作者：
Miyahara, Yoshihiro;Odunsi, Kunle;Wang, Rong-Fu
尽管Th 17细胞在许多自身免疫性疾病的发病机制中起着重要作用，但它们在癌症中的发病率及其产生和调节机制仍不清楚。在这里，我们报告了高百分比的CD 4 + Th 17细胞在卵巢癌部位的存在，而健康供体和癌症患者外周血单核细胞中Th 17细胞的百分比较低。对细胞因子产生谱的分析显示，卵巢肿瘤细胞、肿瘤源性成纤维细胞和抗原呈递细胞（APC）分泌几种关键细胞因子，包括IL-1 β、IL-6、TNF-α和TGF-β，其形成调节和扩增产生人IL-17的T辅助（Th 17）细胞的细胞因子环境。我们进一步表明，IL-β是人类Th 17细胞的分化和扩增所必需的，而IL-6和IL-23也可能在记忆性Th 17细胞的扩增中发挥作用，即使IL-23水平在卵巢癌中很低或检测不到。进一步的实验表明，幼稚或记忆CD 4 + T细胞与肿瘤细胞、APC或两者共培养可以产生高百分比的Th 17细胞。单独用抗IL-1或抗IL-1和抗IL-6的组合治疗降低了肿瘤细胞扩增记忆性Th 17细胞的能力。因此，我们已经确定了一组关键的细胞因子分泌的卵巢肿瘤细胞和肿瘤相关的APC，有利于人类Th 17细胞的产生和扩增。这些发现应该加速努力，以确定这一重要的CD 4 + T细胞亚群在人类对癌症的免疫反应中的功能。
Despite the important role of Th17 cells in the pathogenesis of many autoimmune diseases, their prevalence and the mechanisms by which they are generated and regulated in cancer remain unclear. Here, we report the presence of a high percentage of CD4+ Th17 cells at sites of ovarian cancer, compared with a low percentage of Th17 cells in peripheral blood mononuclear cells from healthy donors and cancer patients. Analysis of cytokine production profiles revealed that ovarian tumor cells, tumor-derived fibroblasts, and antigen-presenting cells (APCs) secreted several key cytokines including IL-1 beta, IL-6, TNF-alpha and TGF-beta, which formed a cytokine milieu that regulated and expanded human IL-17producing T-helper (Th17) cells. We further show that IL-beta was critically required for the differentiation and expansion of human Th17 cells, whereas IL-6 and IL-23 may also play a role in the expansion of memory Th17 cells, even though IL-23 levels are low or undetectable in ovarian cancer. Further experiments demonstrated that coculture of naive or memory CD4+ T cells with tumor cells, APCs, or both could generate high percentages of Th17 cells. Treatment with anti-IL-1 alone or a combination of anti-IL-1 and anti-IL-6 reduced the ability of tumor cells to expand memory Th17 cells. Thus, we have identified a set of key cytokines secreted by ovarian tumor cells and tumor-associated APCs that favor the generation and expansion of human Th17 cells. These findings should accelerate efforts to define the function of this important subset of CD4+ T cells in the human immune response to cancer.