CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice.
CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice.
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DOI：
10.1053/j.gastro.2010.05.007
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发表时间：
2010-09
期刊：
影响因子：
29.4
通讯作者：
Robson SC
中科院分区：
文献类型：
--
作者：
Sun X;Wu Y;Gao W;Enjyoji K;Csizmadia E;Müller CE;Murakami T;Robson SC
腺苷介导免疫抑制，由血管内皮细胞和调节性T细胞（Treg）上表达的外核苷酸酶CD 39（ENTPD 1）和CD 73产生。尽管肿瘤浸润性免疫细胞包括Foxp 3 + Treg，但尚不清楚Treg的局部腺苷生成是否以CD 39依赖性方式促进肿瘤生长。在这项研究中，我们研究了CD 39表达的影响，调节性T细胞对效应免疫细胞的反应，肝转移瘤在体内。肝转移癌的模型是通过门静脉输注表达Cd 39的黑色素瘤B16/F10细胞和MCA 38结肠癌细胞的野生型和突变型小鼠来建立的。使用Cd 39无效或野生型（wt）C57 BL 6供体和辐射受体小鼠通过骨髓移植（BMT）产生嵌合小鼠。我们证明，黑色素瘤转移性肿瘤的肝生长在小鼠与CD 39空血管或在野生型小鼠循环CD 39空骨髓来源的细胞被强烈抑制。我们在体外和体内显示了CD 4 + Foxp 3 + Treg上的功能性CD 39表达抑制了NK细胞介导的抗肿瘤免疫。最后，通过POM-1（聚氧乙烯酸-1）（NTPD酶活性的药理学抑制剂）抑制CD 39活性显著抑制肿瘤生长（P < .001）。Treg上的⑶ 39表达抑制NK活性并且允许转移性生长。对CD 39酶活性的药理学或靶向抑制可用作继发性肝脏恶性肿瘤的辅助治疗。
Adenosine mediates immune suppression and is generated by the ectonucleotidases CD39 (ENTPD1) and CD73 that are expressed on vascular endothelial cells and regulatory T cells (Treg). Although tumor-infiltrating immune cells include Foxp3+ Treg, it is not clear whether local adenosine generation by Treg promotes tumor growth in a CD39-dependent manner. In this study, we have examined the impact of CD39 expression by Treg on effector immune cell responses to hepatic metastases in vivo. A model of hepatic metastatic cancer was developed with portal vein infusion of luciferase-expressing melanoma B16/F10 cells and MCA38 colon cancer cells in wild type and mutant mice null for Cd39. Chimeric mice were generated by bone marrow transplantation (BMT) using Cd39 null or wild type (wt) C57BL6 donors and irradiated recipient mice. We demonstrate that hepatic growth of melanoma metastatic tumors was strongly inhibited in mice with Cd39 null vasculature or in wild type mice with circulating Cd39 null bone marrow-derived cells. We show functional CD39 expression on CD4+Foxp3+ Treg suppressed anti-tumor immunity mediated by NK cells in vitro and in vivo. Lastly, inhibition of CD39 activity by POM-1 (polyoxometalate-1), a pharmacological inhibitor of NTPDase activity, significantly inhibited tumor growth (P < .001). CD39 expression on Treg inhibits NK activity and is permissive for metastatic growth. Pharmacological or targeted inhibition of CD39 enzymatic activity may find utility as an adjunct therapy for secondary hepatic malignancies.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
20.3
作者：
Borsellino, Giovanna;Kleinewietfeld, Markus;Falk, Kirsten
通讯作者：
Falk, Kirsten
影响因子：
3.7
作者：
Chari, Ravi S.;Helton, W. Scott;Marsh, Robert D.
通讯作者：
Marsh, Robert D.
CD4+ CD25+调节性T细胞以转化的生长因子β依赖性方式抑制天然杀伤细胞的功能。
影响因子：
15.3
作者：
Ghiringhelli, F;Ménard, C;Terme, M;Flament, C;Taieb, J;Chaput, N;Puig, PE;Novault, S;Escudier, B;Vivier, E;Lecesne, A;Robert, C;Blay, JY;Bernard, J;Caillat-Zucman, S;Freitas, A;Tursz, T;Wagner-Ballon, O;Capron, C;Vainchencker, W;Martin, F;Zitvogel, L
通讯作者：
Zitvogel, L
DOI：
10.4049/jimmunol.0900475
发表时间：
2009-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hilchey SP;Kobie JJ;Cochran MR;Secor-Socha S;Wang JC;Hyrien O;Burack WR;Mosmann TR;Quataert SA;Bernstein SH
通讯作者：
Bernstein SH