Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes.
Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes.
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DOI：
10.1158/0008-5472.can-08-1921
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发表时间：
2009-02-15
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：
Rodriguez PC;Ernstoff MS;Hernandez C;Atkins M;Zabaleta J;Sierra R;Ochoa AC
在肾细胞癌（RCC）患者的外周血中，产生端粒酶I的髓源性抑制细胞（MDSC）增加。MDSC通过降低L-精氨酸的可用性来抑制T细胞功能，因此被认为是重要的肿瘤逃逸机制。我们的目的是确定肾细胞癌患者中产生精氨酸酶I的MDSC的起源，并确定用于消耗细胞外L-精氨酸的机制。结果显示，人MDSC是活化的多形核细胞（PMN）的亚群，表达高水平的CD 66 b、CD 11 b和VEGFR 1以及低水平的CD 62 L和CD 16。与鼠MDSC相反，人MDSC不通过增加其摄取来消耗l-精氨酸，而是将精氨酸酶I释放到循环中。正常PMN的激活诱导类似于MDSC的表型和功能变化，并且还促进胞内颗粒释放β-淀粉酶I。有趣的是，尽管正常PMN的激活通常以凋亡结束，但与自体PMN或从正常对照获得的PMN相比，MDSC显示凋亡没有增加。高水平的VEGF已经显示出增加癌症患者中的抑制性未成熟髓样树突状细胞。然而，用抗VEGF抗体贝伐单抗治疗RCC患者并不能减少MDSC在外周血中的积累。与此相反，在治疗中加入白细胞介素-2增加了外周血中MDSC的数量和血浆中的谷胱甘肽酶I水平。这些结果可能为肿瘤诱导的无反应性/耐受性机制提供新的见解，并可能有助于解释为什么一些免疫疗法不能诱导抗肿瘤反应。
Myeloid-derived suppressor cells (MDSC) producing arginase I are increased in the peripheral blood of patients with renal cell carcinoma (RCC). MDSC inhibit T-cell function by reducing the availability of l-arginine and are therefore considered an important tumor escape mechanism. We aimed to determine the origin of arginase I–producing MDSC in RCC patients and to identify the mechanisms used to deplete extracellular l-arginine. The results show that human MDSC are a subpopulation of activated polymorphonuclear (PMN) cells expressing high levels of CD66b, CD11b, and VEGFR1 and low levels of CD62L and CD16. In contrast to murine MDSC, human MDSC do not deplete l-arginine by increasing its uptake but instead release arginase I into the circulation. Activation of normal PMN induces phenotypic and functional changes similar to MDSC and also promotes the release of arginase I from intracellular granules. Interestingly, although activation of normal PMN usually ends with apoptosis, MDSC showed no increase in apoptosis compared with autologous PMN or PMN obtained from normal controls. High levels of VEGF have been shown to increase suppressor immature myeloid dendritic cells in cancer patients. Treatment of RCC patients with anti-VEGF antibody bevacizumab, however, did not reduce the accumulation of MDSC in peripheral blood. In contrast, the addition of interleukin-2 to the treatment increased the number of MDSC in peripheral blood and the plasma levels of arginase I. These results may provide new insights on the mechanisms of tumor-induced anergy/tolerance and may help explain why some immunotherapies fail to induce an antitumor response.