α-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3.
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.
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan 11271;
Jing-Rong
JR
Huang
Yi-Chien
YC
Tsai
Ya-Jen
YJ
Chang
Jen-Chien
JC
Wu
Jung-Tung
JT
Hung
Kun-Hsien
KH
Lin
Chi-Huey
CH
Wong
Alice L
AL
Yu
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D001119:Arginase / Q000235:genetics; D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D017635:Clonal Anergy / Q000276:immunology; D051767:Early Growth Response Protein 2 / Q000096:biosynthesis; D051776:Early Growth Response Protein 3 / Q000096:biosynthesis; D053222:Fas Ligand Protein / Q000096:biosynthesis; D005260:Female; D005699:Galactosylceramides / Q000276:immunology* / Q000627:therapeutic use; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis / Q000378:metabolism; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C118387:Cblb protein, mouse; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C497369:Egr3 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005699:Galactosylceramides; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; C493154:alpha-galactosylceramide; D016179:Granulocyte Colony-Stimulating Factor; D051776:Early Growth Response Protein 3; D050721:Proto-Oncogene Proteins c-cbl; C544448:Arg1 protein, mouse; D001119:Arginase