Molecular mimicry of MAGE-A6 and HF-2 epitopes in the induction of antitumor CD8 T-cell responses.

A promising vaccine strategy for the treatment of cancer involves the use of vaccines incorporating tumor antigen-derived synthetic peptides that can be coordinately recognized by specific CD4 and CD8 T-cells. Previously, we reported that a MAGE-A6-derived peptide (MAGE-A6) and its highly-immunogenic and cross-reactive homolog derived from HF-2 permease (HF-2) are promiscuously presented by multiple HLA-DR alleles to responder CD4 T-cells obtained from healthy donors and melanoma patients. Here, we investigated whether these same peptides could concomitantly stimulate cross-reactive MAGE-A6-specific CD8 T-cell responses using cells isolated from HLA-A*0201 (HLA-A2) healthy individuals and patients with melanoma. We now show that MAGE-A6 and, even more so, HF-2, induce memory CD8 T cells that recognize HLA-A2 MAGE-A6 tumor target cells. The immunogenicity of these peptides was at least partially attributed to their embedded MAGE-A6 and HF-2 "homologous" sequences. The functional avidity of HF-2 peptide-primed CD8 T cells for the MAGE-A6 peptide was more than 100-fold greater than that of CD8 T cells primed with the corresponding MAGE-A6 peptide. Additionally, these 2 peptides were recognized in interferon γ (IFNγ) and granzyme B ELISPOT assays by CD8 T-cell clones displaying variable T-cell receptor (TCR) Vβ usage. These data suggest that the immune cross-reactivity of the MAGE-A6 and HF-2 peptides extends to CD8 T cells, at least in HLA-A2 donors, and supports the potential translational utility of these epitopes in clinical vaccine formulations and for immunomonitoring of cancer patients.