Immune regulation by CD8(+) Treg cells: novel possibilities for anticancer immunotherapy
Immune regulation by CD8(+) Treg cells: novel possibilities for anticancer immunotherapy
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CD8( ) Treg 细胞的免疫调节：抗癌免疫治疗的新可能性
DOI：
10.1038/cmi.2018.170
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发表时间：
2018
影响因子：
24.1
通讯作者：
Wang Fang
中科院分区：
文献类型：
--
作者：
Zhang Shuping;Wu Meng;Wang Fang
细胞和分子免疫学高级在线出版物，2018年3月5日; https：//doi。org/10.1038/cmi。2018.170调节性T（Treg）细胞包括免疫抑制细胞的不同亚群，在调节免疫稳态和预防自身免疫中发挥关键作用。在癌症中，Treg细胞可以抑制抗肿瘤免疫应答并支持免疫抑制性肿瘤微环境的建立，从而促进免疫逃避和癌症进展。1 Treg细胞在肿瘤微环境中增加或激活，这与不良的临床结果相关。2虽然CD 4 + Treg细胞已被广泛研究，但缺乏区分CD 8 + Treg细胞与常规CD 8 + T细胞的通用标志物，这意味着CD 8 + Treg细胞在癌症中的功能尚未完全表征。现在，越来越多的研究表明，CD 8 + Treg细胞（CD 8 + CD 25 + Foxp 3+、CD 25 + CD 122 + Foxp 3+和CD 8 + CD 28 −）3-5在肿瘤微环境中积累并抑制抗肿瘤免疫（图1）。然而，CD 8 + Treg细胞对卵巢癌（OC）肿瘤进展的影响尚不清楚。此外，描述参与诱导CD 8 + Treg细胞的分子特征的研究数量有限。最近，我们确定了从OC患者的外周血和新鲜肿瘤组织中分离的CD 8 + T细胞中Treg标志物的表达。我们检测到OC患者中CD 8 + Treg细胞的百分比高于良性卵巢肿瘤患者和健康对照。6免疫抑制性T细胞标志物CD 25、细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和Foxp 3在这些细胞中上调，而免疫活化标志物CD 28的表达在这些细胞中下调。我们还发现，CD 8 + T细胞中Foxp 3的水平与OC患者的肿瘤分期呈正相关，表明CD 8 + Foxp 3 + Treg细胞有助于OC的进展。这突出了CD 8 + Foxp 3 + Treg细胞作为OC患者临床结果的预测因子的作用。然后，我们确定肿瘤微环境是否具有将CD 8+效应T细胞转化为抑制细胞的能力。我们观察到transwell共培养系统中的CD 8 + T细胞与OC肿瘤组织中获得的CD 8 + T细胞的表型相似性，包括上调Foxp 3和CTLA-4，下调CD 28表达水平。[6]体外诱导的CD 8 + Treg细胞也分泌更高浓度的转化生长因子β1（TGF-β1）、干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α和白细胞介素（IL）− 2。Foxp 3 + CTLA-4+和TGF-β1+表型表明诱导的CD 8 + Treg细胞功能活化，这通过它们能够部分抑制TGF-β 1和IFN-γ诱导的CD 4 + T细胞增殖来证实。这些数据表明，CD 8 + Treg细胞在体内OC组织中积累并在体外可诱导，可能会抑制抗肿瘤免疫并有助于肿瘤免疫逃避。TGF-β1在Treg细胞的发育中也起着至关重要的作用，7并且TGF-β信号传导途径缺陷的CD 4 + CD 25 − T细胞不能转化为Foxp 3 + iTreg细胞。8我们发现OC SKOV 3细胞通过分泌TGF-β 1诱导CD 8 + Treg细胞，OC患者表达高水平的TGF-β1，相应地，在CD 8 + T细胞和SKOV 3的共培养系统的上清液中证实了TGF-β1的分泌增加。此外，OC中TGF-β1水平与CD 8 + Treg细胞百分比呈正相关。9与以前的报道一致，10我们还证实了高表达TGF-β1至少部分...
Cellular and Molecular Immunology advance online publication, 5 March 2018; https://doi. org/10.1038/cmi. 2018.170 Regulatory T (Treg) cells comprise diverse subsets of immunosuppressive cells that play a pivotal role in regulating immune homeostasis and preventing autoimmunity. In cancers, Treg cells can suppress antitumor immune responses and support the establishment of an immunosuppressive tumor micro-environment, thus promoting immune evasion and cancer progression. 1 Treg cells are increased or activated in the tumor microenvironment, which is associated with a poor clinical outcome. 2 Although CD4+ Treg cells have been extensively studied, the lack of universal markers to distinguish CD8+ Treg cells from conventional CD8+ T cells means that the function of CD8+ Treg cells in cancer has not been fully characterized. Now, an increasing body of research has revealed that CD8+ Treg cells (CD8+ CD25+ Foxp3+, CD25+ CD122+ Foxp3+ and CD8+ CD28−) 3-5 accumulate in the tumor microenvironment and suppress antitumor immunity (Fig. 1). However, the influence of CD8+ Treg cells on tumor progression in ovarian cancer (OC) is less clear. Moreover, there are a limited number of studies describing the molecular signatures involved in the induction of CD8+ Treg cells. We recently identified the expression of Treg markers in CD8+ T cells isolated from peripheral blood and fresh tumor tissues of OC patients. We detected a higher percentage of CD8+ Treg cells in OC patients compared with benign ovarian tumor patients and healthy controls. 6 The immune-suppressive T-cell markers CD25, cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Foxp3 were upregulated, whereas expression of the immune activation marker CD28 was downregulated in these cells. We also showed that levels of Foxp3 in CD8+ T cells were positively associated with tumor stage in OC patients, suggesting that CD8+ Foxp3+ Treg cells contribute to the progression of OC. This highlights the role of CD8+ Foxp3+ Treg cells as predictors of clinical outcome in OC patients. Then we determined whether the tumor microenvironment had the ability to convert CD8+ effector T cells into suppressor cells. We observed phenotypic similarities between CD8+ Tcells in transwell co-culture system and CD8+ T cells obtained from OC tumor tissues, including upregulated Foxp3 and CTLA-4 and downregulated CD28 expression levels. 6 The in vitroinduced CD8+ Treg cells also secreted higher concentrations of transforming growth factor β1 (TGF-β1), interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)− 2. The Foxp3+ CTLA-4+ and TGF-β1+ phenotype indicated that the induced CD8+ Treg cells were functionally activated, which was confirmed by their ability to suppress CD4+ T-cell proliferation partially by TGF-β1and IFN-γ. These data imply that CD8+ Treg cells accumulated in OC tissue in vivo and inducible in vitro may dampen antitumor immunity and contribute to tumor immune evasion. TGF-β1 also has a crucial role in the development of Treg cells, 7 and CD4+ CD25− T cells deficient in the TGF-β signaling pathway cannot be converted into Foxp3+ iTreg cells. 8 We showed that OC SKOV3 cells induced CD8+ Treg cells by secreting TGF-β1and that OC patients expressed high levels of TGF-β1, correspondingly, increased TGFβ1 secretion was demonstrated in supernatant from the co-culture system of CD8+ T cells and SKOV3. Additionally, TGF-β1 levels were positively correlated with the percentage of CD8+ Treg cells in OC. 9 Consistent with previous reports, 10 we also confirmed that high expression TGF-β1 at least partially …