Molecular identification of GD3 as a suppressor of the innate immune response in ovarian cancer.
Tumors often display mechanisms to avoid or suppress immune recognition. One such mechanism is the shedding of gangliosides into the local tumor microenvironment, and a high concentration of circulating gangliosides is associated with poor prognosis. In this study, we identify ganglioside GD3, which was isolated from the polar lipid fraction of ovarian cancer-associated ascites, as an inhibitory factor that prevents innate immune activation of natural killer T (NKT) cells. Purified GD3 displayed a high affinity for both human and mouse CD1d, a molecule involved in the presentation of lipid antigens to T cells. Purified GD3, as well as substances within the ascites, bound to the CD1d antigenic-binding site and did not require additional processing for its inhibitory effect on NKT cells. Importantly, in vivo administration of GD3 inhibited α-galactosylceramide (α-GalCer)-induced NKT cell activation in a dose-dependent manner. These data therefore indicate that ovarian cancer tumors may use GD3 to inhibit the antitumor NKT cell response as an early mechanism of tumor immune evasion.
Department of Pathology and The Kelly Gynecologic Oncology Service, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21201, USA. twebb@som.umaryland.edu
Tonya J
TJ
Webb
Xiangming
X
Li
Robert L
RL
Giuntoli
Pablo H H
PH
Lopez
Christoph
C
Heuser
Ronald L
RL
Schnaar
Moriya
M
Tsuji
Christian
C
Kurts
Mathias
M
Oelke
Jonathan P
JP
Schneck
D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism / Q000502:physiology; D001201:Ascites / Q000473:pathology; D002277:Carcinoma / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005732:Gangliosides / Q000302:isolation & purification* / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology
D055610:Antigens, CD1d; C526877:CD1D protein, human; D005732:Gangliosides; C026226:ganglioside, GD3