| Enhanced anti-tumor effects by chemical modified iGb3 analogues via increasing stability of the CD1d/antigen/TCR ternary complex and IFN-{gamma} signaling of NKT cells. | |
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MedLine Citation:
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PMID: 21653685 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Certain glycolipid antigens for natural killer T (NKT) cells can direct the overall cytokine balance of the immune response. However, the molecular mechanism of Th1 or Th2-baised cytokine secretion by NKT cells is still unknown. Previously, we synthesized iGb3 analogues by introducing a hydroxyl group at C4 on the ceramide portion of iGb3 to produce 4-HO-iGb3, or further deoxylation on the terminal galactose to produce 4' ''-dh-iGb3. Both modified iGb3, especially 4'''-dh-iGb3, stimulated more interferon (IFN)-γ production by hepatic NKT cells and thus elicited preferential Th1 responses. Here, we found that 4'''-dh-iGb3-loaded bone marrow-derived dendritic cells (DC) could significantly inhibit growth of subcutaneous melanoma and suppress lung metastasis in C57BL/6 mice compared to unmodified iGb3-loaded DCs. In investigating the mechanisms of this improved activity, we found that 4'''-dh-iGb3 stimulation increased STAT1 signaling by NKT cells, while the phosphorylation of Th2 type cytokines associated transcription factor STAT6 signaling were not affected. Analysis of the structures of iGb3 and 4'''-dh-iGb3 revealed that 4'''-dh-iGb3 provides greater stability and affinity between glycolipid and CD1d or NKT TCR complex than iGb3. Thus, 4'''-dh-iGb3 can improve the anti-tumor effects of a DC-based vaccine possibly by stabilizing the CD1d/glycolipid/TCR complex and stimulating IFN-γ signaling of NKT cells. Furthermore, chemical modification of iGb3 can elicit Th1-biased responses by NKT cells, and 4'''-dh-iGb3 combined with a DC vaccine may serve as a potent new NKT-based therapy against tumors and infectious diseases. |
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Authors:
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Zhixia Zhou; Cai Zhang; Chengfeng Xia; Wenlan Chen; Huawei Zhu; Pingping Shang; Fang Ma; Peng George Wang; Jian Zhang; Wenfang Xu; Zhigang Tian |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-6-8 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: - ISSN: 1538-8514 ISO Abbreviation: - Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-6-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1School of Pharmaceutical Sciences, Shandong University, Institute of Immunopharmacology & Immunotherapy. |
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