α-Galactosylceramide but Not Phenyl-Glycolipids Induced NKT Cell Anergy and IL-33–Mediated Myeloid-Derived Suppressor Cell Accumulation via Upregulation of egr2/3

Fas配体 下调和上调 自然杀伤性T细胞 免疫系统 免疫疗法 癌症研究 髓源性抑制细胞 脾脏 免疫学 细胞生物学 程序性细胞死亡 抑制器 T细胞 生物 化学 癌症 细胞凋亡 生物化学 遗传学 基因
作者
Jing-Rong Huang,Yi-Chien Tsai,Ya‐Jen Chang,Jen-Chien Wu,Jung‐Tung Hung,Kun‐Hsien Lin,Chi‐Huey Wong,Alice L. Yu
出处
期刊:Journal of Immunology [The American Association of Immunologists]
卷期号:192 (4): 1972-1981 被引量:44
标识
DOI:10.4049/jimmunol.1302623
摘要

Strategies for cancer immunotherapy include activating immune system for therapeutic benefit or blockade of immune checkpoints. To harness innate immunity to fight cancer, α-galactosylceramide (α-GalCer) has been used to activate NKT cells. Unfortunately, administration of α-GalCer causes long-term NKT cell anergy, but the molecular mechanism is unclear. In this study, we showed that α-GalCer-triggered egr2/3, which induced programmed death 1 and cbl-b in NKT cells, leading to NKT cell anergy. We also uncovered the induction of the immunosuppressive myeloid-derived suppressor cells (MDSCs) in the spleen by α-GalCer that might attenuate its antitumor efficacy. The accumulation of MDSC was accompanied by 20-fold rise in their arg-1 mRNAs and enhanced expression of programmed death 1/programmed death ligand 1. Furthermore, α-GalCer-induced egr-2/3 in hepatic NKT cells upregulated their TRAIL in addition to Fas ligand (FasL) and induced alarm signaling molecule IL-33 in Kupffer cells, presumably because of liver damage triggered by TRAIL/FasL. We further demonstrated that IL-33-stimulated macrophages produce G-CSF, which in turn, boosted MDSCs. Thus, α-GalCer-induced FasL/TRAIL and IL-33 provided a novel mechanism underlying α-GalCer-induced hepatotoxicity and MDSC accumulation. In contrast, analogs of α-GalCer containing phenyl group in the lipid tail could neither induce NKT anergy nor enhance MDSCs accumulation. Furthermore, tumor-infiltrating MDSCs in mice injected repeatedly with α-GalCer were 2-fold higher than those treated with phenyl-glycolipids. These results not only revealed the induction of MDSC via IL-33 as a new mechanism for α-GalCer-elicited immunosuppression but also provided one of the mechanisms underlying the superior antitumor potency of phenyl-glycolipids. Our findings have important implications for the development of NKT-stimulatory glycolipids as vaccine adjuvants and anticancer therapeutics.

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