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[Cancer Research 59, 3134-3142, July 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 3134-3142, July 1, 1999]
© 1999 American Association for Cancer Research

Immunology

Generation of Human T-cell Responses to an HLA-A2.1-restricted Peptide Epitope Derived from {alpha}-Fetoprotein1

Lisa H. Butterfield, Andrew Koh, Wilson Meng, Charles M. Vollmer, Antoni Ribas, Vivian Dissette, Eric Lee, John A. Glaspy, William H. McBride and James S. Economou2

Divisions of Surgical Oncology [L. H. B., A. K., W. M., C. M. V., A. R., V. D., E. L., J. S. E.], Hematology/Oncology [A. R., J. A. G.], and Experimental Radiation Oncology [W. H. M.], University of California Los Angeles Medical Center, University of California Los Angeles, Los Angeles, California 90095

{alpha}-Fetoprotein (AFP) is often derepressed in human hepatocellular carcinoma. Peptide fragments of AFP presented in the context of major histocompatibility molecules could serve as potential recognition targets by CD8 T cells, provided these lymphocytes were not clonally deleted in ontogeny. We therefore wished to determine whether the human T-cell repertoire could recognize AFP-derived peptide epitopes in the context of a common class I allele, HLA-A2.1. Dendritic cells genetically engineered to express AFP were capable of generating AFP-specific T-cell responses in autologous human lymphocyte cultures and in HLA-A2.1/Kb transgenic mice. These T cells recognize a 9-mer peptide derived from the AFP protein hAFP542–550 (GVALQTMKQ). Identified as a potential A2.1-restricted peptide epitope from a computer analysis of the AFP sequence, hAFP542–550 proved to have low binding affinity to A2.1, but slow off-kinetics. AFP-specific CTL- and IFN-{gamma}-producing cells recognize hAFP542–550-pulsed targets. Conversely, hAFP542–550 peptide-generated T cells from both human lymphocyte cultures and A2.1/Kb transgenic mice recognized AFP-transfected targets in both cytotoxicity assays and cytokine release assays. These lines of evidence clearly demonstrate that AFP-reactive clones have not been deleted from the human T-cell repertoire and identify one immunodominant A2.1-restricted epitope. These findings also clearly establish AFP as a potential target for T-cell-based immunotherapy.




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Copyright © 1999 by the American Association for Cancer Research.