Differences in frequency distribution of HLA-A2 subtypes between North American and Italian white melanoma patients: relevance for epitope specific vaccination protocols.

Abstract

Cytotoxic T lymphocytes (CTL) associated in vivo with tumor regression recognize the product of nonmutated genes expressed by most melanoma cells as peptides bound to human leukocyte antigen (HLA) molecules. Multiple HLA-A*0201 restricted peptides derived from melanoma associated antigens (MAA) have been described, and peptide-based vaccination protocols against melanoma are being developed worldwide for the treatment of HLA-A2 melanoma patients based on the assumption that most serologically typed HLA-A2+ individuals will be suitable for such vaccinations. Serologic typing of HLA-A2, however, encompasses a family of at least 17 related alleles recognized by molecular typing techniques and differing at one or more functional residues of the HLA class I molecule. We have recently shown that naturally occurring single-residue variants of HLA-A*0201 are responsible for significant differences in CTL response to MAA-peptide stimulation. Existing data for HLA-A*02 subtype frequencies among whites (who are most affected by melanoma) derive from analyses of Northern European and North American populations that are of similar heritage and predict an exceedingly rare (< 5%) frequency of non-HLA-A*0201 alleles. Melanoma however, affects other white populations in which the prevalence of HLA-A*02 alleles could be more variable. This study was done to identify HLA-A*02 subtypes and their prevalence in two ancestrally different white melanoma populations. HLA-A*02 subtype frequencies were compared by polymerase chain reaction between serologically HLA-A2+ melanoma patients referred for treatment to the Istituto Nazionale Tumori of Milan (n = 93), Italy or the National Cancer Institute, Bethesda, MD, U.S.A. (n = 100). This analysis demonstrated differences in subtype specificity and distribution between the two populations, with a significantly higher percentage of non HLA-A*0201 subtypes in the Italian population. Only 2% of serologically HLA-A2+ Northern American white melanoma patients did not express HLA-A*0201. In contrast, 15% of HLA-A2+ Italian patients were not HLA-A*0201 (p2 value = 0.001). As allele-specific/peptide-based vaccination protocols are presently pursued at several institutions, a proportion of patients might be inappropriately enrolled basing their eligibility on serologically defined HLA-typing.