Tumor gangliosides inhibit the tumor-specific immune response.
Tumor gangliosides are highly immunosuppressive membrane glycosphingolipids that are shed into the tumor cell microenvironment. We directly tested the impact of shed gangliosides on the in vivo antitumor immune response in a syngeneic fully autochthonous system (FBL-3 erythroleukemia cells, C57BL/6 mice, and highly purified FBL-3 cell gangliosides). The major FBL-3 ganglioside was identified as GM1b by mass spectrometry. Substantial ganglioside shedding (90 pmol/108 cells/h), a requisite for their inhibition of the immune function of tumor-infiltrating leukocytes, was detected. Immunosuppression by FBL-3 gangliosides was potent; 5-20 microM inhibited the tumor-specific secondary proliferative response (80-100%) and suppressed the generation of tumor-specific CTLs (97% reduction of FBL-3 cell lysis at an E:T ratio of 100:1). In vivo, coinjection of 10 nmol of FBL-3 gangliosides with a primary FBL-3 cell immunization led to a reduced response to a secondary challenge (the increase in the draining popliteal lymph node mass, cell number, and lymphocyte thymidine incorporation were lowered by 70, 69, and 72%, respectively). Coinjection of gangliosides with a secondary tumor challenge led to a 61, 74, and 42% reduction of the increase in lymph node mass, cell number, and thymidine uptake and a 63-74% inhibition of the increase of draining lymph node T cells (CD3+), B cells (CD19+), and dendritic cells/macrophages (Mac-3+). Overall, the clear conclusion that tumor-derived gangliosides inhibit syngeneic antitumor immune responses implicates these molecules as a potent factor in promoting tumor formation and progression.
McKallip
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R
Glycobiology Program, Center for Cancer and Transplantation Biology, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine, Washington, DC 20010, USA.
Li
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R
Ladisch
S
S
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005677:G(M1) Ganglioside / Q000031:analogs & derivatives / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology; D005732:Gangliosides / Q000276:immunology* / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism
D005732:Gangliosides; D007166:Immunosuppressive Agents; D005677:G(M1) Ganglioside; C029624:ganglioside M1b