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* Department of Immunology,
Neurosurgery, and
Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263;
Institute of Immunotherapy for Cancer, Kinki University, Osaka, Japan; and
¶ Faculty of Biotechnology, Jagiellonian University, Krakow, Poland
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.
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1 This work was supported by the National Institutes of Health grants R21EB008071 (to D.K.) and R21NS054167 (to R.A.F.), and by funds to commemorate Dr. Goro Chihara’s research activity.
2 A.W. and M.G. contributed equally to this work.
3 Current address: Department of Biochemistry and Molecular Biology, University of Medical Sciences, Poznan, Poland.
4 Address correspondence and reprint requests to Dr. Danuta Kozbor, Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: danuta.kozbor{at}roswellpark.org
5 Abbreviations used in this paper: DC, dendritic cell; ACT, adoptive cell transfer; BM, bone marrow; RFU, relative fluorescence unit; MMP-2, matrix metalloproteinase-2; ALCAM, activated leukocyte cell adhesion molecule; FAK, focal adhesion kinase; shRNA, short-hairpin RNA; RNAi, RNA interference.
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  M. Gil, M. Bieniasz, A. Wierzbicki, B. J. Bambach, H. Rokita, and D. Kozbor Targeting a Mimotope Vaccine to Activating Fc{gamma} Receptors Empowers Dendritic Cells to Prime Specific CD8+ T Cell Responses in Tumor-Bearing Mice J. Immunol., November 15, 2009; 183(10): 6808 - 6818. [Abstract] [Full Text] [PDF]
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