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首页> 外文期刊>Journal of immunotherapy >Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells.
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Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells.

机译：白介素2介导的卵巢癌相关CD4 +调节性T细胞转化为促炎性白介素17产生的辅助T细胞。

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摘要

Epithelial ovarian cancer (EOC) is a highly inflammatory malignancy, characterized by the presence, at the tumor site, of regulatory T cells (Treg) that suppress antitumor immunity. Recently, a new lineage of CD4+ T cells producing the proinflammatory cytokine interleukin (IL)-17 [T helper (TH) 17] has been identified as a major player in some autoimmune diseases. The role of TH17 cells in cancer, however, and their relationship with coexisting Treg populations, whose differentiation is partially controlled by the same mediators (ie, transforming growth factor-beta), are yet unclear. Here, we show that EOC-associated/infiltrating lymphocytes derived by culturing tumor samples in the presence of IL-2 contain significant frequencies of TH17 cells, coproducing interferon-gamma (IFN)-gamma and tumor necrosis factor (TNF)-alpha, which represent, in some cases, up to 40% of total CD4+ T cells. TH17 cells were also detected ex vivo, but at lower proportions than in cultured tumor-infiltrating lymphocytes/tumor-associated lymphocytes, and were confined to the CD4+CD25- fraction. Remarkably, analysis of EOC-associated conventional CD4CD25 T cell and Treg populations isolated ex vivo from tumor samples by cell sorting and cultured with tumor-associated CD3- cells in the presence of IL-2 revealed that EOC Treg stimulated under these conditions were rapidly converted into TH17 cells, down-regulated FOXP3 expression, and lost their suppressive capacity. Thus, although the impact of TH17 cells on the evolution of EOC remains to be established, our data suggest that local IL-2 treatment in ovarian cancer may result in the conversion of tumor-associated Treg into TH17 cells, relieve Treg-mediated suppression, and contribute to enhance antitumor immunity.
机译：上皮性卵巢癌（EOC）是一种高度炎症性恶性肿瘤，其特征是在肿瘤部位存在抑制抗肿瘤免疫力的调节性T细胞（Treg）。最近，已确定产生促炎性细胞因子白介素（IL）-17 [T辅助（TH）17]的CD4 + T细胞新谱系是某些自身免疫性疾病的主要参与者。然而，目前尚不清楚TH17细胞在癌症中的作用及其与Treg群体共存的关系，Treg群体的分化部分受同一介质（即转化生长因子-β）控制。在这里，我们显示，通过在IL-2存在下培养肿瘤样品而获得的EOC相关/浸润淋巴细胞包含大量的TH17细胞，共同产生干扰素-γ（IFN）-γ和肿瘤坏死因子（TNF）-α，在某些情况下，最多代表总CD4 + T细胞的40％。还可以离体检测TH17细胞，但其比例低于培养的肿瘤浸润淋巴细胞/肿瘤相关淋巴细胞中的比例，并局限于CD4 + CD25-部分。值得注意的是，通过细胞分选并从肿瘤样品中离体分离并在IL-2存在下与肿瘤相关的CD3-细胞一起培养的EOC相关的常规CD4CD25 T细胞和Treg群体的分析显示，在这些条件下刺激的EOC Treg可以快速转化进入TH17细胞，下调FOXP3表达，并失去其抑制能力。因此，尽管TH17细胞对EOC进化的影响尚待确定，但我们的数据表明，卵巢癌中局部IL-2治疗可能导致肿瘤相关Treg转化为TH17细胞，缓解Treg介导的抑制作用，并有助于增强抗肿瘤免疫力。

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