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α-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3.

Abstract
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.
AuthorsJing-Rong Huang, Yi-Chien Tsai, Ya-Jen Chang, Jen-Chien Wu, Jung-Tung Hung, Kun-Hsien Lin, Chi-Huey Wong, Alice L Yu
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 4 Pg. 1972-81 (Feb 15 2014) ISSN: 1550-6606 [Electronic] United States
PMID24465013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • B7-H1 Antigen
  • Cblb protein, mouse
  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • Egr3 protein, mouse
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Galactosylceramides
  • Il33 protein, mouse
  • Interleukin-33
  • Interleukins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • RNA, Messenger
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • alpha-galactosylceramide
  • Granulocyte Colony-Stimulating Factor
  • Early Growth Response Protein 3
  • Proto-Oncogene Proteins c-cbl
  • Arg1 protein, mouse
  • Arginase
Topics
  • Adaptor Proteins, Signal Transducing (biosynthesis)
  • Animals
  • Antineoplastic Agents (metabolism, therapeutic use)
  • Arginase (genetics)
  • B7-H1 Antigen (biosynthesis, metabolism)
  • Cell Line, Tumor
  • Clonal Anergy (immunology)
  • Early Growth Response Protein 2 (biosynthesis)
  • Early Growth Response Protein 3 (biosynthesis)
  • Fas Ligand Protein (biosynthesis)
  • Female
  • Galactosylceramides (immunology, therapeutic use)
  • Granulocyte Colony-Stimulating Factor (biosynthesis, metabolism)
  • Immunosuppression Therapy
  • Immunotherapy
  • Interleukin-33
  • Interleukins (metabolism)
  • Kupffer Cells (metabolism)
  • Lymphocyte Activation (immunology)
  • Macrophages (immunology, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells (cytology, immunology)
  • Natural Killer T-Cells (immunology, metabolism)
  • Programmed Cell Death 1 Receptor (biosynthesis, metabolism)
  • Proto-Oncogene Proteins c-cbl (biosynthesis)
  • RNA, Messenger (biosynthesis)
  • Spleen (immunology)
  • TNF-Related Apoptosis-Inducing Ligand (biosynthesis)
  • Up-Regulation

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