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Ascites Specific Inhibition of CD1d-Mediated Activation of Natural Killer T Cells

Authors' Affiliations: ¹ Department of Pathology and ² The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland

Requests for reprints: Tonya J. Webb, Johns Hopkins School of Medicine, Ross Building, Room 644S, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-502-7131; Fax: 410-614-3548; E-mail: twebb5{at}jhmi.edu.

Purpose: Natural killer T (NKT) cells recognize lipid antigen presented by CD1 molecules. NKT cells can both directly, through cytotoxicity, and indirectly, through activation of other effector cells, mediate antitumor immunity. It has been shown, however, that tumor-associated lipids are frequently shed into the tumor microenvironment, which can mediate immunosuppressive activity. Given that ovarian cancer–associated ascites has been reported to have increased levels of gangliosides, we examined the effect of tumor-associated and other ascites on CD1d-mediated antigen presentation to NKT cells.

Experimental Design: To investigate the effects of ascites on NKT cell activation, we pretreated CD1d-expressing cells with the ascites and measured their ability to stimulate cytokine production in NKT cells. To determine whether antigen processing or editing was necessary, CD1d-immunoglobulin–based artificial antigen presenting cells (aAPC) were also incubated with ascites. In addition, to examine specificity, we analyzed whether ascites fluid could influence the activation of classic CD8⁺ T cells.

Results: Pretreatment of CD1d-expressing cells with ascites from the majority of patients inhibited the ability of the cells to stimulate/activate NKT cells in a dose-dependent manner. Ascites treatment also partially blocked the ability of -galactosylceramide–loaded CD1d-immunoglobulin–based aAPC to activate NKT cells. In addition, our data show that treatment with ascites does not inhibit HLA-A2–mediated activation of classic CD8⁺ T cells.

Conclusions: Together, these data suggest that ovarian and other cancers may have developed immune evasion mechanisms specifically targeting the CD1/NKT cell system.