Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: A mechanism of tumor evasion
Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: A mechanism of tumor evasion
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DOI：
10.1158/0008-5472.can-04-4505
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Ochoa, AC
中科院分区：
文献类型：
--
作者：
Zea, AH;Rodriguez, PC;Ochoa, AC
在结肠癌和肺癌小鼠的肿瘤和脾脏中发现了具有高端粒酶活性的髓样抑制细胞。这些细胞被描述为巨噬细胞或未成熟树突细胞，消耗精氨酸并损害T细胞增殖和细胞因子产生。尽管已经描述了癌症患者中的精氨酸酶活性，但认为其起源于肿瘤细胞将精氨酸代谢为维持快速细胞增殖所需的鸟氨酸。本研究的目的是确定在肾细胞癌患者中是否存在产生高水平端粒酶的髓系抑制细胞。来自123名转移性肾细胞癌患者的外周血单个核细胞在治疗前被发现具有显著增加的脱氢酶活性。这些患者的细胞因子产生明显减少，T细胞受体CD 3 ζ链表达水平低。细胞分离研究表明，增加的CD 11b+、CD 14-、CD 15+细胞的活性仅限于具有多形粒细胞形态和标志物的特定亚群，而不是小鼠模型中描述的巨噬细胞或树突状细胞。此外，这些患者血浆中精氨酸水平低，鸟氨酸水平高。CD 11b+、CD 14-骨髓抑制细胞的耗尽重建了T细胞增殖和CD 3链表达。这些结果首次表明，在人类癌症患者中存在抑制性髓样细胞，其可产生抗肿瘤酶。此外，它支持了这样一个概念，即阻断β-内酰胺酶可能是免疫治疗成功的重要一步。
Myeloid suppressor cells with high arginase activity are found in tumors and spleen of mice with colon and lung cancer. These cells, described as macrophages or immature dendritic cells, deplete arginine and impair T cell proliferation and cytokine production. Although arginase activity has been described in cancer patients, it is thought to originate from tumor cells metabolizing arginine to ornithine needed to sustain rapid cell proliferation. The goal of this study was to determine whether myeloid suppressor cells producing high arginase existed in renal cell carcinoma patients. Peripheral blood mononuclear cells from 123 patients with metastatic renal cell carcinoma, prior to treatment, were found to have a significantly increased arginase activity. These patients had a markedly decreased cytokine production and expressed low levels of T cell receptor CD3 zeta chain. Cell separation studies showed that the increased arginase activity was limited to a specific subset of CD11b+, CD14-, CD15+ cells with a polymorphonuclear granulocyte morphology and markers, instead of macrophages or dendritic cells described in mouse models. Furthermore, these patients had low levels of arginine and high levels of ornithine in plasma. Depletion of the CD11b+, CD14- myeloid suppressor cells reestablished T cell proliferation and CD3 chain expression. These results showed, for the first time, the existence of suppressor myeloid cells producing arginase in human cancer patients. In addition, it supports the concept that blocking arginase may be an important step in the success of immunotherapy.