Department of Dermatology, University of Alabama, Birmingham, AL 35294, USA.
J Immunol. 2010 Mar 1;184(5):2281-8. doi: 10.4049/jimmunol.0902574. Epub 2010 Jan 29.
The role of immune responses in tumor development is a central issue for tumor biology and immunology. IL-17 is an important cytokine for inflammatory and autoimmune diseases. Although IL-17-producing cells are detected in cancer patients and tumor-bearing mice, the role of IL-17 in tumor development is controversial, and mechanisms remain to be fully elucidated. In the current study, we found that the development of tumors was inhibited in IL-17R-deficient mice. A defect in IFN-gammaR increased tumor growth, whereas tumor growth was inhibited in mice that were deficient in both IL-17R and IFN-gammaR compared with wild-type animals. Further experiments showed that neutralization of IL-17 by Abs inhibited tumor growth in wild-type mice, whereas systemic administration of IL-17 promoted tumor growth. The IL-17R deficiency increased CD8 T cell infiltration, whereas it reduced the infiltration of myeloid-derived suppressor cells (MDSCs) in tumors. In contrast, administration of IL-17 inhibited CD8 T cell infiltration and increased MDSCs in tumors. Further analysis indicated that IL-17 was required for the development and tumor-promoting activity of MDSCs in tumor-bearing mice. These data demonstrate that IL-17-mediated responses promote tumor development through the induction of tumor-promoting microenvironments at tumor sites. IL-17-mediated regulation of MDSCs is a primary mechanism for its tumor-promoting effects. The study provides novel insights into the role of IL-17 in tumor development and has major implications for targeting IL-17 in treatment of tumors.
免疫反应在肿瘤发生发展中的作用是肿瘤生物学和免疫学的核心问题。IL-17 是炎症和自身免疫性疾病的重要细胞因子。尽管在癌症患者和荷瘤小鼠中检测到了产生 IL-17 的细胞，但 IL-17 在肿瘤发生发展中的作用仍存在争议，其机制仍有待充分阐明。在本研究中，我们发现 IL-17R 缺陷小鼠的肿瘤生长受到抑制。IFN-γR 的缺陷增加了肿瘤的生长，而与野生型动物相比，IL-17R 和 IFN-γR 均缺陷的小鼠的肿瘤生长受到抑制。进一步的实验表明，Abs 中和 IL-17 抑制了野生型小鼠的肿瘤生长，而 IL-17 的全身给药促进了肿瘤的生长。IL-17R 的缺乏增加了 CD8 T 细胞的浸润，而减少了肿瘤中髓系来源的抑制细胞（MDSCs）的浸润。相反，IL-17 的给药抑制了 CD8 T 细胞的浸润，并增加了肿瘤中的 MDSCs。进一步的分析表明，IL-17 是荷瘤小鼠中 MDSCs 的发育和促进肿瘤活性所必需的。这些数据表明，IL-17 介导的反应通过诱导肿瘤部位的肿瘤促进微环境促进肿瘤的发生发展。IL-17 对 MDSCs 的调节是其促进肿瘤作用的主要机制。该研究为 IL-17 在肿瘤发生发展中的作用提供了新的见解，并为靶向 IL-17 治疗肿瘤提供了重要依据。
