IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis.
IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis.
复制标题
DOI：
10.1038/nature14282
复制
发表时间：
2015-06-18
期刊：
影响因子：
64.8
通讯作者：
de Visser, Karin E.
中科院分区：
文献类型：
--
作者：
Coffelt, Seth B.;Kersten, Kelly;Doornebal, Chris W.;Weiden, Jorieke;Vrijland, Kim;Hau, Cheei-Sing;Verstegen, Niels J. M.;Ciampricotti, Metamia;Hawinkels, Lukas J. A. C.;Jonkers, Jos;de Visser, Karin E.
转移性疾病仍然是乳腺癌患者死亡的主要原因。转移级联的不同步骤依赖于癌细胞与其微环境之间的相互作用。已知在这种局部微环境和远处器官中，免疫细胞及其介质会促进转移的形成。然而，肿瘤诱导的全身性炎症对转移的确切贡献和调节全身性炎症的机制知之甚少。在这里，我们表明，在自发性乳腺癌转移的小鼠模型中，肿瘤通过引发全身炎症级联反应来最大化转移的机会。我们从机制上证明，白细胞介素（IL）-1β刺激γ δ（γδ）T细胞表达IL-17，导致全身性粒细胞集落刺激因子（G-CSF）依赖性扩增和嗜中性粒细胞极化的小鼠乳腺肿瘤。肿瘤诱导的中性粒细胞获得抑制携带CD 8抗原的细胞毒性T淋巴细胞的能力，这限制了转移的建立。IL-17或G-CSF的中和和γδ T细胞的缺乏防止中性粒细胞积聚并下调中性粒细胞的T细胞抑制表型。此外，γδ T细胞或中性粒细胞的缺乏显著减少了肺和淋巴结转移，而不影响原发性肿瘤进展。我们的数据表明，靶向免疫系统中这种新的癌细胞启动的多米诺骨牌效应-γδ T细胞/IL-17/中性粒细胞轴-代表了抑制转移性疾病的新策略。
Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation,. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1β elicits IL-17 expression from gamma delta (γδ) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of γδ T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Moreover, the absence of γδ T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system—the γδ T cell/IL-17/neutrophil axis—represents a new strategy to inhibit metastatic disease.
登录
查看更多内容
影响因子：
28.2
作者：
Novitskiy SV;Pickup MW;Gorska AE;Owens P;Chytil A;Aakre M;Wu H;Shyr Y;Moses HL
通讯作者：
Moses HL
影响因子：
82.9
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：
7.3
作者：
Ciampricotti, Metamia;Vrijland, Kim;de Visser, Karin E.
通讯作者：
de Visser, Karin E.
影响因子：
3.7
作者：
Azab, Basem;Bhatt, Vijaya R.;Widmann, Warren D.
通讯作者：
Widmann, Warren D.