NK细胞乙酰肝素酶:抗肿瘤免疫

The Journal of Clinical Investigation

2017-06-05Article

12.784

影响因子

原标题:NK细胞乙酰肝素酶控制肿瘤浸润和免疫监视

① 新鲜分离的小鼠和人NK细胞表达低水平的内-β-D-葡糖醛酸酶乙酰肝素酶,当NK细胞活化时其表达水平升高;② NK细胞内缺乏乙酰肝素酶的小鼠(Hpsefl/fl NKp46-iCre),致癌剂甲基胆蒽(MCA)处理后极易发生肿瘤,Hpsefl/fl NKp46-iCre小鼠淋巴瘤细胞株RMA-S-RAE-1β移植瘤模型生长更快;③ NK细胞在原发灶内的浸润及转移部位的募集严格依赖于乙酰肝素酶的存在,当NK细胞缺乏乙酰肝素酶时,转移灶的细胞因子和免疫检查点阻断免疫治疗无效。

NK细胞 乙酰肝素酶 甲基胆蒽

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Title:
NK cell heparanase controls tumor invasion and immune surveillance

DOI:
10.1172/JCI92958

Abstract & Authors展开

Abstract:
NK cells are highly efficient at preventing cancer metastasis but are infrequently found in the core of primary tumors. Here, have we demonstrated that freshly isolated mouse and human NK cells express low levels of the endo-β-D-glucuronidase heparanase that increase upon NK cell activation. Heparanase deficiency did not affect development, differentiation, or tissue localization of NK cells under steady-state conditions. However, mice lacking heparanase specifically in NK cells (Hpsefl/fl NKp46-iCre mice) were highly tumor prone when challenged with the carcinogen methylcholanthrene (MCA). Hpsefl/fl NKp46-iCre mice were also more susceptible to tumor growth than were their littermate controls when challenged with the established mouse lymphoma cell line RMA-S-RAE-1β, which overexpresses the NK cell group 2D (NKG2D) ligand RAE-1β, or when inoculated with metastatic melanoma, prostate carcinoma, or mammary carcinoma cell lines. NK cell invasion of primary tumors and recruitment to the site of metastasis were strictly dependent on the presence of heparanase. Cytokine and immune checkpoint blockade immunotherapy for metastases was compromised when NK cells lacked heparanase. Our data suggest that heparanase plays a critical role in NK cell invasion into tumors and thereby tumor progression and metastases. This should be considered when systemically treating cancer patients with heparanase inhibitors, since the potential adverse effect on NK cell infiltration might limit the antitumor activity of the inhibitors.

All Authors:
Eva M Putz,Alyce J Mayfosh,Kevin Kos,Deborah S Barkauskas,Kyohei Nakamura,Liam Town,Katharine J Goodall,Dean Y Yee,Ivan Kh Poon,Nikola Baschuk,Fernando Souza-Fonseca-Guimaraes,Mark D Hulett,Mark J Smyth

First Authors:
Eva M Putz

Correspondence:
Mark D Hulett,Mark J Smyth

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