Unconventional glycosphingolipid or non-glycosphingolipid endogenous tumor lipid antigens recognized by CD1d-restricted NKT cells

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NCI	IMMUNO/INFLAM-24

* FARE Award Winner

Authors

• S Parish
• K Muindi
• M Oakley
• M Suzuki
• R Tatituri
• M Brenner
• J Berzofsky
• M Terabe

Abstract

NKT cells recognize lipid antigens presented by CD1d. Two types exist within this subset. Previously, mouse tumor models (15-12 and CT26) demonstrated that NKT cells are critical in regulating tumor immunity without a stimulation of NKT cells by exogenous antigens, suggesting endogenous tumor lipid antigens exist. Although glycosphingolipids are thought to be the dominant endogenous antigens, those antigens remained unknown. In a two-pronged approach, the first arm created a thrombin-cleavable CD1d transfected tumor line, allowing for the removal of the CD1d/lipid complex without the use of detergents. Both native CD1d and thrombin-CD1d transfected 15-12 tumor cells activated both type I and type II NKT cell hybridomas, confirming an endogenous tumor lipid antigen exists. The second arm presented CD1d dimer loaded with fractionated lipids of CT26 or 15-12RM to a NKT hybridoma-panel. A CT26 fraction, which contains predominately glycosphingolipids and phospholipids, activated two type I NKT hybridomas. Unexpected loss of activity upon glycosphingolipid-enrichment suggests either a non-glycosphingolipid or unconventional glycosphingolipid is the predominant lipid antigen. Ultimately, this work points the field to consider that unconventional glycosphingolipids or non- glycosphingolipid lipids may be the major endogenous tumor antigens responsible for NKT cell activation, providing potential targets for cancer immunotherapy involving NKT cells.

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