Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids.
Alpha-galactosylceramide (alpha-GalCer), a glycolipid that stimulates natural killer T (NKT) cells to produce both T helper (Th)1 and Th2 cytokines, has shown antitumor effects in mice but failed in clinical trials. We evaluated 16 analogs of alpha-GalCer for their CD1-mediated T cell receptor (TCR) activation of naïve human NKT cells and their anticancer efficacy. In vitro, glycolipids containing an aromatic ring in their acyl tail or sphingosine tail were more effective than alpha-GalCer in inducing Th1 cytokines/chemokines, TCR activation, and human NKT cell expansion. None of these glycolipids could directly stimulate human dendritic cell maturation, except for a glycolipid with an aromatic ring on the sphingosine tail. Here, we show that glycolipids activated the TCR of NKT cells with phosphorylation of CD3epsilon, ERK1/2, or CREB, which correlated with their induction of Th1 cytokines. Notably, the extent of NKT cell activation when glycolipid was presented by antigen-presenting cells was greater than when glycolipid was presented by non-antigen-presenting cells. In vivo, in mice bearing breast or lung cancers, the glycolipids that induced more Th1-biased cytokines and CD8/CD4 T cells displayed significantly greater anticancer potency than alpha-GalCer. These findings indicate that alpha-GalCer analogs can be designed to favor Th1-biased immunity, with greater anticancer efficacy and other immune-enhancing activities than alpha-GalCer itself.
Chang
Ya-Jen
YJ
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
Huang
Jing-Rong
JR
Tsai
Yi-Chien
YC
Hung
Jung-Tung
JT
Wu
Douglass
D
Fujio
Masakazu
M
Wong
Chi-Huey
CH
Yu
Alice L
AL
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017252:CD3 Complex / Q000032:analysis / Q000378:metabolism; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D018925:Chemokines / Q000032:analysis / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006017:Glycolipids / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*; D006367:HeLa Cells; D006801:Humans; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D000970:Antineoplastic Agents; D017252:CD3 Complex; D018925:Chemokines; D016207:Cytokines; D006017:Glycolipids; D011948:Receptors, Antigen, T-Cell; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3