Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells
Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells
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DOI：
10.1007/s00262-008-0591-5
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发表时间：
2009-05-01
影响因子：
5.8
通讯作者：
Yang, Rongcun
中科院分区：
文献类型：
--
作者：
Liu, Yu;Yu, Yinyan;Yang, Rongcun
在荷瘤小鼠和人中，Gr-1（+）CD 11b（+）髓源性抑制细胞（MDSC）数量增加，并与免疫抑制相关。在肿瘤环境中MDSC产生精氨酸酶I可能是免疫抑制和肿瘤逃避的中心机制。在本研究和之前的研究中，我们发现来自卵巢18 D癌小鼠腹水和脾脏的Gr-1（+）CD 11b（+）MDSCs高水平表达PD-1、CTLA-4、B7-H1和CD 80，而未检测到其他共刺激分子，即CD 40、B7-DC和CD 86。进一步的研究表明，Gr-1（+）CD 11b（+）MDSCs上的PD-1和CTLA-4可调节CD 11b（+）MDSCs上CD 11 a酶I的活性和表达。阻断和沉默PD-1、CTLA-4或PD-1和CTLA-4分子均能显著降低肿瘤相关因子诱导的端粒酶I活性和表达。当它们的配体B7-H1和/或CD 80被阻断或沉默时，也观察到类似的结果。此外，CD 80缺陷也降低了CD 80 I的表达和活性。PD-I、CTLA-4或两者的抗体阻断或沉默降低了PD-I +CTLA-4+ MDSC的抑制潜力。阻断PD-1、CTLA-4或两者也减缓了肿瘤生长，提高了荷瘤小鼠的存活率。因此，MDSC之间可能存在一种以共抑制和共刺激分子为基础的免疫调节系统。
An elevated number of Gr-1(+)CD11b(+) myeloid-derived suppression cells (MDSCs) has been described in mice and human bearing tumor and associated with immune suppression. Arginase I production by MDSCs in the tumor environment may be a central mechanism for immunosuppression and tumor evasion. In this study and before, we found that Gr-1(+)CD11b(+) MDSCs from ascites and spleen of mice bearing ovarian 18D carcinoma express a high level of PD-1, CTLA-4, B7-H1 and CD80 while other co-stimulatory molecules, namely CD40, B7-DC and CD86 are not detected. Further studies showed that PD-1 and CTLA-4 on the Gr-1(+)CD11b(+) MDSCs regulated the activity and expression of arginase I. The blockage and silencing of PD-1, CTLA-4 or both PD-1 and CTLA4 molecules could significantly reduce arginase I activity and expression induced with tumor-associated factor. Similar results were also observed while their ligands B7-H1 and/or CD80 were blocked or silenced. Furthermore, CD80 deficiency also decreased the arginase I expression and activity. Antibody blockade or silencing of PD-1, CTLA-4 or both reduced the suppressive potential of PD-1+CTLA-4+MDSCs. Blockade of PD-1, CTLA-4 or both also slowed tumor growth and improved the survival rate of tumor-bearing mice. Thus, there may exist a coinhibitory and costimulatory molecules-based immuno-regulating wet among MDSCs.