Autologous
melanoma-specific CTL recognize a common
tumor-associated Ag (TAA) in the context of HLA
class I antigens. We have demonstrated that
HLA-A2 can be a restricting Ag and, in T cell lines homozygous for
HLA-A2, that CTL can be generated by stimulation with
HLA-A2 allogeneic
melanomas. In the current study, we have investigated T cell lines from patients who are heterozygous at
HLA-A region locus, to determine the relative importance of each A-region allele in this MHC-restricted recognition of
tumor. We have shown that
HLA-A1 can be a restricting Ag, and that allogeneic
melanomas expressing
HLA-A1 can substitute for the autologous
tumor in the generation of HLA-A1-restricted CTL. However, when T cell lines express both
HLA-A1 and
HLA-A2, the
HLA-A2 allele governed restriction of the
melanoma TAA. Three autologous-stimulated
HLA-A1, A2 CTL lines all demonstrated restriction by the
HLA-A2 allele, when examined in cytotoxicity assays, cold-competition assays, and proliferation assays. There was no evidence of restriction by the second HLA-allele,
HLA-A1. Although the autologous-stimulated CTL use a single A-region allele for
tumor recognition, the autologous
HLA-A1, A2
tumors are lysed by both HLA-A1-restricted and HLA-A2-restricted CTL. The dominance of restricting alleles was further demonstrated when HLA-matched allogeneic
melanomas were used as the stimulating
tumor to generate
tumor-specific CTL. Stimulation of the heterozygous (HLA-A1, A2) lymphocytes with HLA-A2-matched allogeneic
melanomas resulted in CTL specific for the autologous
tumor, and restricted by the
HLA-A2 Ag. However, stimulation with an HLA-A1-matched allogeneic
melanoma failed to induce
tumor-specific CTL restricted by the
HLA-A1 Ag. The data suggest there is a dominance of
HLA-A region Ag at the level of the T cell, such that only one is restricting in the recognition of the autologous
melanoma. At the level of the
tumor, however, the TAA is expressed in the context of both
HLA-A region alleles. We can generate specific CTL from lymph node cells or PBL and
HLA-A region matched allogeneic
melanomas; however, because most patients are heterozygous at the
HLA-A region locus, an understanding of the dominant restricting alleles must be obtained so that an appropriately matched allogeneic
melanoma can be selected.