Immunization with a mimotope of GD2 ganglioside induces CD8+ T cells that recognize cell adhesion molecules on tumor cells.

Abstract

The GD2 ganglioside expressed on neuroectodermal tumor cells has been used as a target for passive and active immunotherapy in patients with malignant melanoma and neuroblastoma. We have reported that immunization of mice with a 47-LDA mimotope of GD2, isolated from a phage display peptide library with anti-GD2 mAb 14G2a, induces MHC class I-restricted CD8(+) T cell responses to syngeneic neuroblastoma tumor cells. The cytotoxic activity of the vaccine-induced CTLs was independent of GD2 expression, suggesting recognition of a novel tumor-associated Ag cross-reacting with 47-LDA. Glycan microarray and immunoblotting studies using 14G2a mAb demonstrated that this Ab is highly specific for the entire carbohydrate motif of GD2 but also cross-reacts with a 105 kDa glycoprotein expressed by GD2(+) and GD2(-) neuroblastoma and melanoma cells. Functional studies of tumor cells grown in three-dimensional collagen cultures with 14G2a mAb showed decreases in matrix metalloproteinase-2 activation, a process regulated by the 105 kDa-activated leukocyte cell adhesion molecule (ALCAM/CD166). A recombinant CD166 glycoprotein was shown to be recognized by 14G2a Ab and inhibition of CD166 expression by RNA interference ablated the cell sensitivity to lysis by 47-LDA-induced CD8(+) T cells in vitro and in vivo. The binding of 14G2a to CD166 was not disruptable by a variety of exo- and endo-glycosidases, implying recognition of a non-glycan epitope on CD166. These results suggest that the vaccine-induced CTLs recognize a 47-LDA cross-reactive epitope expressed by CD166, and reveal a novel mechanism of induction of potent tumor-specific cellular responses by mimotopes of tumor-associated carbohydrate Ags.

• Authors: Andrzej Wierzbicki, Margaret Gil, Michael Ciesielski, Robert A Fenstermaker, Yutaro Kaneko, Hanna Rokita, Joseph T Lau, Danuta Kozbor
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 181 Issue 9 Pg. 6644-53 (Nov 01 2008) ISSN: 1550-6606 [Electronic] United States
• PMID: 18941255 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Activated-Leukocyte Cell Adhesion Molecule
• Cancer Vaccines
• Epitopes, T-Lymphocyte
• Gangliosides
• ganglioside, GD2

Topics

• Activated-Leukocyte Cell Adhesion Molecule (immunology, metabolism)
• Animals
• Antigen Presentation (immunology)
• CD8-Positive T-Lymphocytes (immunology, metabolism, transplantation)
• Cancer Vaccines (administration & dosage, immunology)
• Cell Line, Tumor
• Cells, Cultured
• Epitopes, T-Lymphocyte (administration & dosage, immunology, metabolism)
• Female
• Ganglia, Spinal (immunology, metabolism)
• Ganglioglioma (immunology, metabolism)
• Gangliosides (administration & dosage, immunology)
• Humans
• Immunotherapy, Adoptive (methods)
• Lymphocyte Activation (immunology)
• Melanoma (immunology, metabolism)
• Mice
• Mice, Inbred A
• Molecular Mimicry (immunology)
• Neuroblastoma (immunology, metabolism)