Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University-, Medical College, Soochow University, Suzhou 215123, China.
Immunology Program, Department of Microbiology and Immunology, National University of Singapore, Singapore 117456, Singapore.
J Immunol. 2018 Dec 15;201(12):3770-3779. doi: 10.4049/jimmunol.1800627. Epub 2018 Nov 16.
IL-33 released by epithelial cells and immune cells functions as an alarmin and can induce both type 1 and type 2 immune responses. However, the role of IL-33 release in tumor development is still not clear. In this study, we examined the function of released IL-33 in murine hepatocellular carcinoma (HCC) models by hydrodynamically injecting either IL-33-expressing tumor cells or IL-33-expressing plasmids into the liver of tumor-bearing mice. Tumor growth was greatly inhibited by IL-33 release. This antitumor effect of IL-33 was dependent on suppression of tumorigenicity 2 (ST2) because it was diminished in ST2 mice. Moreover, HCC patients with high IL-33 expression have prolonged overall survival compared with the patients with low IL-33 expression. Further study showed that there were increased percentages and numbers of activated and effector CD4 and CD8 T cells in both spleen and liver in IL-33-expressing tumor-bearing mice. Moreover, IFN-γ production of the CD4 and CD8 T cells was upregulated in both spleen and liver by IL-33. The cytotoxicity of CTLs from IL-33-expressing mice was also enhanced. In vitro rIL-33 treatment could preferentially expand CD8 T cells and promote CD4 and CD8 T cell activation and IFN-γ production. Depletion of CD4 and CD8 T cells diminished the antitumor activity of IL-33, suggesting that the antitumor function of released IL-33 was mediated by both CD4 and CD8 T cells. Taken together, we demonstrated in murine HCC models that IL-33 release could inhibit tumor development through its interaction with ST2 to promote antitumor CD4 and CD8 T cell responses.
上皮细胞和免疫细胞释放的 IL-33 作为警报素，可诱导 1 型和 2 型免疫反应。然而，IL-33 释放在肿瘤发展中的作用尚不清楚。在这项研究中，我们通过向荷瘤小鼠的肝脏中水力注射表达 IL-33 的肿瘤细胞或表达 IL-33 的质粒，研究了释放的 IL-33 在小鼠肝细胞癌 (HCC) 模型中的功能。IL-33 的释放极大地抑制了肿瘤的生长。IL-33 的这种抗肿瘤作用依赖于 ST2 的抑制，因为在 ST2 小鼠中这种作用减弱。此外，高表达 IL-33 的 HCC 患者的总生存期长于低表达 IL-33 的患者。进一步的研究表明，在表达 IL-33 的荷瘤小鼠的脾脏和肝脏中，激活和效应性 CD4 和 CD8 T 细胞的比例和数量均增加。此外，IL-33 在脾脏和肝脏中上调了 CD4 和 CD8 T 细胞的 IFN-γ 产生。来自表达 IL-33 的小鼠的 CTL 的细胞毒性也增强了。体外 rIL-33 处理可以优先扩增 CD8 T 细胞，并促进 CD4 和 CD8 T 细胞的激活和 IFN-γ 的产生。耗尽 CD4 和 CD8 T 细胞会减弱 IL-33 的抗肿瘤活性，表明释放的 IL-33 的抗肿瘤功能是由 CD4 和 CD8 T 细胞介导的。总之，我们在小鼠 HCC 模型中证明，IL-33 的释放可以通过与 ST2 相互作用来促进抗肿瘤 CD4 和 CD8 T 细胞反应，从而抑制肿瘤的发展。
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