Molecular Identification of GD3 as a Suppressor of the Innate Immune Response in Ovarian Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 15; pp. 3744 - 3752
• Main Authors: WEBB, Tonya J, XIANGMING LI, GIUNTOLI, Robert L, LOPEZ, Pablo H. H, HEUSER, Christoph, SCHNAAR, Ronald L, TSUJI, Moriya, KURTS, Christian, OELKE, Mathias, SCHNECK, Jonathan P
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-08-2012
• Subjects: Animals; Antigens, CD1d - metabolism; Antigens, CD1d - physiology; Antineoplastic agents; Ascites - pathology; Biological and medical sciences; Carcinoma - immunology; Carcinoma - pathology; Cells, Cultured; Down-Regulation - drug effects; Down-Regulation - immunology; Female; Female genital diseases; Gangliosides - isolation & purification; Gangliosides - pharmacology; Gangliosides - physiology; Gynecology. Andrology. Obstetrics; Humans; Immunity, Innate - drug effects; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lymphocyte Activation - drug effects; Medical sciences; Mice; Mice, Inbred C57BL; Ovarian Neoplasms - immunology; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Tumor Escape - drug effects; Tumor Escape - immunology; Tumors; Ovarian diseases; Immune response; Ovary cancer; Natural immunity; Suppressor; Identification; Malignant tumor; Cancer; Female genital diseases
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-2695

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.