Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues
Zhou, Zhixia1; Zhang, Cai1; Xia, Chengfeng3; Chen, Wenlan4,5; Zhu, Huawei2; Shang, Pingping1; Ma, Fang1; Wang, Peng George4,5; Zhang, Jian1; Xu, Wenfang2; Tian, Zhigang1,6
Corresponding AuthorZhang, C (reprint author), Shandong Univ, Inst Immunopharmacol & Immunotherapy, Sch Pharmaceut Sci, 44 Wenhua,West Rd, Jinan 250012, Peoples R China
AbstractCertain 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-biased cytokine secretion by NKT cells is still unknown. Previously, we synthesized isoglobotrihexosylceramide (iGb3) analogues by introducing a hydroxyl group at C4 on the ceramide portion of iGb3 to produce 4-HO-iGb3 or to further deoxylation on the terminal galactose to produce 4'"-dh-iGb3. Both modified iGb3, especially 4'"-dh-iGb3, stimulated more IFN-gamma 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 with 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, whereas the phosphorylation of Th2 type cytokine-associated transcription factor STAT6 signaling was 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 antitumor effects of a DC-based vaccine possibly by stabilizing the CD1d/glycolipid/TCR complex and stimulating IFN-gamma 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. Mol Cancer Ther; 10(8); 1375-84. (C) 2011 AACR.
KeywordV-alpha-14i Nkt Cells Killer T-cells Ifn-gamma Production Alpha-galactosylceramide Autoimmune Encephalomyelitis Immune-responses Dendritic Cells Activation Bet Gata-3
Subject AreaOncology
Indexed BySCI
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000293692500008
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Cited Times:3[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Affiliation1.Shandong Univ, Inst Immunopharmacol & Immunotherapy, Sch Pharmaceut Sci, Jinan 250012, Peoples R China
2.Shandong Univ, Inst Med Chem, Sch Pharmaceut Sci, Jinan 250012, Peoples R China
3.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources W China, Kunming, Peoples R China
4.Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA
5.Ohio State Univ, Dept Chem, Columbus, OH 43210 USA
6.Univ Sci & Technol China, Dept Microbiol & Immunol, Sch Life Sci, Hefei 230026, Peoples R China
Recommended Citation
GB/T 7714
Zhou, Zhixia,Zhang, Cai,Xia, Chengfeng,et al. Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues[J]. MOLECULAR CANCER THERAPEUTICS,2011,10(8):1375-1384.
APA Zhou, Zhixia.,Zhang, Cai.,Xia, Chengfeng.,Chen, Wenlan.,Zhu, Huawei.,...&Tian, Zhigang.(2011).Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues.MOLECULAR CANCER THERAPEUTICS,10(8),1375-1384.
MLA Zhou, Zhixia,et al."Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues".MOLECULAR CANCER THERAPEUTICS 10.8(2011):1375-1384.
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