TY - JOUR
T1 - Ascites specific inhibition of CDId-mediated activation of natural Killer T Cells
AU - Webb, Tonya J.
AU - Giuntoli, Robert L.
AU - Rogers, Ophelia
AU - Schneck, Jonathan
AU - Oelke, Mathias
PY - 2008/12/1
Y1 - 2008/12/1
N2 - 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 NKTcells. Experimental Design: To investigate the effects of ascites on NKTcell 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-immuno-globulin-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 + Tcells. 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 α-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 + Tcells. Conclusions: Together, these data suggest that ovarian and other cancers may have developed immune evasion mechanisms specifically targeting the CD1/NKTcell system.
AB - 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 NKTcells. Experimental Design: To investigate the effects of ascites on NKTcell 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-immuno-globulin-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 + Tcells. 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 α-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 + Tcells. Conclusions: Together, these data suggest that ovarian and other cancers may have developed immune evasion mechanisms specifically targeting the CD1/NKTcell system.
UR - http://www.scopus.com/inward/record.url?scp=59449106344&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=59449106344&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-08-1468
DO - 10.1158/1078-0432.CCR-08-1468
M3 - Article
C2 - 19047090
AN - SCOPUS:59449106344
SN - 1078-0432
VL - 14
SP - 7652
EP - 7658
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -