Ascites specific inhibition of CD1d-mediated activation of natural killer T cells.
OBJECTIVE
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.


METHODS
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 alpha-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.
Webb
Tonya J
TJ
Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA. twebb5@jhmi.edu
Giuntoli
Robert L
RL
Rogers
Ophelia
O
Schneck
Jonathan
J
Oelke
Mathias
M
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D055610:Antigens, CD1d / Q000378:metabolism*; D001201:Ascites / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism
D055610:Antigens, CD1d; D016207:Cytokines