Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (ASTAR), Singapore 138673, Singapore.
Cell Rep. 2024 Mar 26;43(3):113835. doi: 10.1016/j.celrep.2024.113835. Epub 2024 Feb 26.
Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.
白细胞介素-37 (IL-37) 已被证明可抑制多种癌症类型的肿瘤生长。然而，IL-37 在肿瘤微环境中的免疫调节功能尚不清楚。在这里，我们建立了一个人类白细胞抗原-I (HLA-I) 匹配的人源化患者衍生异种移植肝癌 (HCC) 模型和三个鼠原位 HCC 模型，以研究 IL-37 在肿瘤微环境中的功能。我们发现 IL-37 抑制 HCC 生长并促进 T 细胞激活。进一步的研究表明，IL-37 损害了髓系来源抑制细胞 (MDSC) 的免疫抑制能力。在过继转移前用 IL-37 预处理 MDSC 可减弱其在 HCC 荷瘤小鼠中的促肿瘤作用。此外，IL-37 促进 MDSC 的糖酵解和氧化磷酸化，导致 ATP 释放增加，从而损害 MDSC 的免疫抑制能力。总之，我们证明了 IL-37 通过代谢重编程抑制肿瘤微环境中 MDSC 的免疫抑制能力来抑制肿瘤的发展，使其成为未来癌症免疫治疗的一个有前途的靶点。
