Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
J Immunol. 2013 Jan 15;190(2):812-20. doi: 10.4049/jimmunol.1103797. Epub 2012 Dec 17.
Evaluation of immune dysfunction during the tumor-bearing state is a critical issue in combating cancer. In this study, we initially found that IL-6, one of the cachectic factors, suppressed CD4(+) T cell-mediated immunity through downregulation of MHC class II by enhanced arginase activity of dendritic cells (DC) in tumor-bearing mice. We demonstrated that administration of Ab against IL-6R (anti-IL-6R mAb) greatly enhanced T cell responses and inhibited the growth of tumor in vivo. We also found that IL-6 upregulated the expression of arginase-1 and arginase activity of DC in vitro. Tumor-infiltrating CD11c(+) DC exhibited upregulated mRNA expression of arginase-1 but reduced expression of MHC class II in parallel with the increase in serum IL-6 levels at the late stage in tumor-bearing hosts. However, the administration of anti-IL-6R mAb into tumor-bearing mice inhibited both the downmodulation of MHC class II and the upregulation of arginase-1 mRNA levels in DC. Furthermore, we noted that N(ω)-hydroxy-L-arginine or L-arginine, an arginase-1 inhibitor, blocked the reduction in MHC class II levels on CD11c(+) DC during the tumor-bearing state. Finally, we demonstrated that the administration of N(ω)-hydroxy-L-arginine at the peritumor site significantly enhanced CD4(+) T cell responses and inhibited tumor growth. Thus, IL-6-mediated arginase activation and the subsequent reduction in MHC class II expression on DC appeared to be critical mechanisms for inducing dysfunction of the immune system in the tumor-bearing state. Blockade of the IL-6-arginase cascade is a promising tool to overcome the dysfunction of antitumor immunity in tumor-bearing hosts.
评估荷瘤状态下的免疫功能障碍是抗肿瘤的关键问题。在本研究中，我们最初发现，作为恶病质因子之一的白细胞介素 6（IL-6）通过增强树突状细胞（DC）的精氨酸酶活性下调 MHC Ⅱ类来抑制 CD4+T 细胞介导的免疫。我们证明，用抗 IL-6R（抗 IL-6R mAb）治疗可显著增强 T 细胞反应并抑制体内肿瘤生长。我们还发现，IL-6 在体外上调了 DC 的 arginase-1 表达和 arginase 活性。在荷瘤宿主晚期，肿瘤浸润性 CD11c+DC 表现出 arginase-1 的 mRNA 表达上调，同时 MHC Ⅱ类表达下调，与血清 IL-6 水平升高平行。然而，向荷瘤小鼠中给予抗 IL-6R mAb 可抑制 DC 中 MHC Ⅱ类下调和 arginase-1 mRNA 水平上调。此外，我们注意到 N（ω）-羟基-L-精氨酸或 L-精氨酸，一种精氨酸酶抑制剂，可阻断荷瘤状态下 CD11c+DC 中 MHC Ⅱ类水平的降低。最后，我们证明在肿瘤周围部位给予 N（ω）-羟基-L-精氨酸可显著增强 CD4+T 细胞反应并抑制肿瘤生长。因此，IL-6 介导的精氨酸酶激活和随后 DC 上 MHC Ⅱ类表达的降低似乎是诱导荷瘤状态下免疫系统功能障碍的关键机制。阻断 IL-6-精氨酸酶级联反应是克服荷瘤宿主抗肿瘤免疫功能障碍的有前途的工具。
