Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress.
Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress.
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DOI：
10.1371/journal.pbio.2004990
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发表时间：
2018-05
期刊：
影响因子：
9.8
通讯作者：
Silva-Santos B
中科院分区：
文献类型：
--
作者：
Mensurado S;Rei M;Lança T;Ioannou M;Gonçalves-Sousa N;Kubo H;Malissen M;Papayannopoulos V;Serre K;Silva-Santos B
最近发现产生白细胞介素 17 (IL-17) 的 γδ T 细胞（γδ17 T 细胞）可促进肿瘤生长和转移形成。然而，如何在肿瘤微环境中调节这种 γδ17 T 细胞反应仍然很大程度上未知。在此，我们报告肿瘤相关中性粒细胞可以通过强烈抑制 γδ17 T 细胞来发挥明显的抗肿瘤作用。肿瘤相关中性粒细胞通过诱导氧化应激抑制小鼠 CD27−Vγ6+γδ17 T 细胞的增殖，从而阻止它们构成肿瘤微环境中促肿瘤 IL-17 的主要来源。从机制上讲，我们发现 CD27− γδ17 T 细胞中抗氧化剂谷胱甘肽的低表达使其特别容易受到中性粒细胞衍生的活性氧 (ROS) 的影响。一致的是，超氧化物缺乏或施用谷胱甘肽前体可挽救体内 CD27−Vγ6+γδ17 T 细胞增殖。此外，人类 Vδ1+ γδ T 细胞（包含癌症患者中发现的大多数 γδ17 T 细胞）也表现出较低的谷胱甘肽水平，并受到 ROS 的有效抑制。因此，这项工作在肿瘤微环境中确定了一个意想不到的、免疫抑制但抗肿瘤的中性粒细胞/ROS/γδ17 T 细胞轴。肿瘤被许多免疫细胞浸润，影响癌症进展和结果的许多方面，包括肿瘤生长、对健康周围组织的侵袭、转移的形成以及对治疗的反应。在肿瘤浸润淋巴细胞中，γδ T 细胞在肿瘤环境中发挥双重功能；那些产生抗肿瘤细胞因子干扰素-γ 的细胞因子具有保护作用，而产生白细胞介素 17 (IL-17) 的细胞因子则支持肿瘤生长。因此，了解哪些机制可能限制 IL-17 偏向的 γδ T 细胞反应至关重要。在这项研究中，我们意外地发现IL-17+ γδ T细胞表达的抗氧化剂谷胱甘肽水平非常低，并且对活性氧（ROS）非常敏感，从而暴露了它们的致命弱点。事实上，当产生 ROS 的中性粒细胞在肿瘤内积聚时，它们会抑制 IL-17+ γδ T 细胞增殖，从而抑制其促肿瘤活性。我们将在小鼠癌症模型中获得的这些发现扩展到人类 γδ T 细胞，因此相信局部氧化应激水平的调节可能具有重要的治疗意义。
Interleukin 17 (IL-17)–producing γδ T cells (γδ17 T cells) have been recently found to promote tumor growth and metastasis formation. How such γδ17 T-cell responses may be regulated in the tumor microenvironment remains, however, largely unknown. Here, we report that tumor-associated neutrophils can display an overt antitumor role by strongly suppressing γδ17 T cells. Tumor-associated neutrophils inhibited the proliferation of murine CD27− Vγ6+ γδ17 T cells via induction of oxidative stress, thereby preventing them from constituting the major source of pro-tumoral IL-17 in the tumor microenvironment. Mechanistically, we found that low expression of the antioxidant glutathione in CD27− γδ17 T cells renders them particularly susceptible to neutrophil-derived reactive oxygen species (ROS). Consistently, superoxide deficiency, or the administration of a glutathione precursor, rescued CD27− Vγ6+ γδ17 T-cell proliferation in vivo. Moreover, human Vδ1+ γδ T cells, which contain most γδ17 T cells found in cancer patients, also displayed low glutathione levels and were potently inhibited by ROS. This work thus identifies an unanticipated, immunosuppressive yet antitumoral, neutrophil/ROS/γδ17 T-cell axis in the tumor microenvironment. Tumors are infiltrated by many immune cells that influence many aspects of cancer progression and outcome, including tumor growth, invasion of healthy surrounding tissues, formation of metastasis, and response to treatments. Among tumor-infiltrating lymphocytes, γδ T cells play dual functions in the tumor milieu; whereas those that produce the antitumor cytokine interferon-γ are protective, their counterparts that make interleukin 17 (IL-17) support tumor growth. It is therefore critical to understand which mechanisms may limit IL-17–biased γδ T-cell responses. In this study, we unexpectedly found that IL-17+ γδ T cells express very low levels of the antioxidant, glutathione, and are very sensitive to reactive oxygen species (ROS), thus revealing their Achilles’ heel. Indeed, as ROS-producing neutrophils accumulate within tumors, they inhibit IL-17+ γδ T-cell proliferation and thereby suppress their pro-tumoral activities. We extended these findings, obtained in mouse models of cancer, to human γδ T cells and therefore believe that the modulation of local levels of oxidative stress may have important therapeutic implications.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
50.3
作者：
Granot Z;Henke E;Comen EA;King TA;Norton L;Benezra R
通讯作者：
Benezra R
影响因子：
64.8
作者：
Finisguerra V;Di Conza G;Di Matteo M;Serneels J;Costa S;Thompson AA;Wauters E;Walmsley S;Prenen H;Granot Z;Casazza A;Mazzone M
通讯作者：
Mazzone M
DOI：
10.4049/jimmunol.0902574
发表时间：
2010-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
He D;Li H;Yusuf N;Elmets CA;Li J;Mountz JD;Xu H
通讯作者：
Xu H
影响因子：
5.5
作者：
Cheemarla, Nagarjuna R.;Del Rocio Banos-Lara, Ma;Guerrero-Plata, Antonieta
通讯作者：
Guerrero-Plata, Antonieta