title: Enhanced antitumor effects by chemical modified IGb3 analogues.
abstract: 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-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-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 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-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.
authors.affiliation: Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Zhou
authors.forename: Cai
authors.initials: C
authors.lastname: Zhang
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Xia
authors.forename: Wenlan
authors.initials: W
authors.lastname: Chen
authors.forename: Huawei
authors.initials: H
authors.lastname: Zhu
authors.forename: Pingping
authors.initials: P
authors.lastname: Shang
authors.forename: Fang
authors.initials: F
authors.lastname: Ma
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005915:Globosides / Q000737:chemistry / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009362:Neoplasm Metastasis; D011485:Protein Binding; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D014281:Trihexosylceramides / Q000737:chemistry / Q000494:pharmacology*; D000098815:T-bet Transcription Factor
chemical_list: D055610:Antigens, CD1d; D000970:Antineoplastic Agents; D005915:Globosides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D050794:STAT1 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014281:Trihexosylceramides; C514781:isoglobotrihexosylceramide