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.
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Authors | Jing-Rong Huang, Yi-Chien Tsai, Ya-Jen Chang, Jen-Chien Wu, Jung-Tung Hung, Kun-Hsien Lin, Chi-Huey Wong, Alice L Yu |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 192
Issue 4
Pg. 1972-81
(Feb 15 2014)
ISSN: 1550-6606 [Electronic] United States |
PMID | 24465013
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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