精氨酸酶
肿瘤微环境
生物
T细胞
癌症研究
髓样
分子生物学
免疫系统
免疫学
精氨酸
生物化学
氨基酸
作者
Paulo C. Rodrı́guez,David Quiceno,Jovanny Zabaleta,Blair Ortiz,Arnold H. Zea,M. Blanca Piazuelo,Alberto Delgado,Pelayo Correa,Jason Brayer,Eduardo M. Sotomayor,Scott Antonia,Juan B. Ochoa,Augusto C. Ochoa
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2004-08-15
卷期号:64 (16): 5839-5849
被引量:1180
标识
DOI:10.1158/0008-5472.can-04-0465
摘要
Abstract T cells infiltrating tumors have a decreased expression of signal transduction proteins, a diminished ability to proliferate, and a decreased production of cytokines. The mechanisms causing these changes have remained unclear. We demonstrated recently that peritoneal macrophages stimulated with interleukin 4 + interleukin 13 produce arginase I, which decreases the expression of the T-cell receptor CD3ζ chain and impairs T-cell responses. Using a 3LL murine lung carcinoma model we tested whether arginase I was produced in the tumor microenvironment and could decrease CD3ζ expression and impair T-cell function. The results show that a subpopulation of mature tumor-associated myeloid cells express high levels of arginase I, whereas tumor cells and infiltrating lymphocytes do not. Arginase I expression in the tumor was seen on day 7 after tumor injection. Tumor-associated myeloid cells also expressed high levels of cationic amino acid transporter 2B, which allowed them to rapidly incorporate l-Arginine (l-Arg) and deplete extracellular l-Arg in vitro. l-Arg depletion by tumor-associated myeloid cells blocked the re-expression of CD3ζ in stimulated T cells and inhibited antigen-specific proliferation of OT-1 and OT-2 cells. The injection of the arginase inhibitor N-hydroxy-nor-l-Arg blocked growth of s.c. 3LL lung carcinoma in mice. High levels of arginase I were also found in tumor samples of patients with non-small cell carcinoma. Therefore, arginase I production by mature myeloid cells in the tumor microenvironment may be a central mechanism for tumor evasion and may represent a target for new therapies.
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