Medullublastoma Expresses CD1d and Can Be Targeted for Immunotherapy with NKT Cells
Liping Song, Daofeng Liu, Leonid Metelitsa. University of Texas Health Center at Houston, Houston, TX; Texas Children's Cancer Center, Houston, TX
Background: Medulloblastoma (MB) is the most common brain tumor of childhood. Current therapies are not curative for a third of patients and have debilitating long-term toxicities.
Design: In this study we analyzed whether MB cells express CD1d, an antigen-presenting molecule for Natural Killer T (NKT) cells and could be targeted for direct NKT-cell cytotoxicity.
Results: We detected cell surface expression of CD1d in two of four human MB cell lines by flow cytometry and CD1d gene expression in the positive cell lines was confirmed by RT-PCR.
The immunohistochemical staining detected CD1d protein expression in 9 of 20 analyzed primary MB specimens. Nearly all tumor cells in the positive specimens expressed CD1d on the cell surface. In contrast, normal brain tissues were CD1d-negative except some vascular endothelial cells. Functional experiments demonstrated that CD1d-positive MB cells could effectively present synthetic type-I NKT cell ligands α-Galactosylceramide or 7DW8-5 as well as an endogenous ligand β-Glucosylceramide to activate NKT-cell cytokine production, proliferation, and cytotoxicity. Ligand-pulsed MB cells were highly sensitive to CD1d-dependent NKT-cell cytotoxicity in vitro, and intracranial injection of human NKT cells resulted in regression of established orthotropic human MB xenografts in NOD/SCID mice.
Importantly, both the numbers and functional properties of peripheral blood type-I NKT cells were preserved in MB patients to the levels similar to those in healthy individuals.
Conclusions: Therefore, CD1d is expressed on tumor cells in about half of MB patients and represents a novel target for immunotherapy of this brain tumor.
Monday, March 4, 2013 11:15 AM
Proffered Papers: Section G2, Monday Morning