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Background: Known risks for development of SCCHN and its progression and recurrence include excessive alcohol use and decreased retinoic acid synthesis. Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) plays a key role in the metabolism of alcohol and retinoic acid. ALDH family members are involved in the conversion of retinal to retinoic acid and acetaldehyde to acetic acid, the second step in alcohol metabolism. Acetaldehyde is a carcinogen. Alterations in the expression of various ALDH family genes in cancer have been noted. Decreased ALDH1 activities in tissues can readily result in elevated levels of acetaldehyde, reduced retinoic acid synthesis and increased risk for SCCHN development. Increased ALDH1A1 function in tumors is associated with resistance to various chemotherapeutic agents, such as cyclophosphamide and cisplatin.

Methods: ALDH1A1 expression in SCCHN cell lines, tumors and normal tissues was determined at the transcriptional and translational levels using real time RT/PCR analysis, immunoblot and immunohistochemistry assays. A fluorescent substrate of ALDH1 was used to measure ALDH1 activity in SCCHN cell lines by flow cytometry. HLA-A2 restricted, CD8+ T cells specific for the ALDH1A188-96 peptide were generated by in vitro stimulation of CD8+ T cells obtained from HLA-A2+ normal donors and subjects with SCCHN using peptide-pulsed autologous dendritic cells. Reactivity of anti-ALDH1A188-96 CD8+ T cells against peptide-pulsed T2 target cells and HLA-A2+ SCCHN cells naturally presenting the epitope was determined in ELISPOT INF-γ and Granzyme B assays.

Results: ALDH1A1 is overexpressed by most but all SCCHN and HLA-A2-restricted, anti-ALDH1A188-96 CD8+ T cells recognize HLA-A2+ SCCHN cell lines overexpressing ALDH1A1, but not those with little to no expression of ALDH1A1.

Conclusion: The identification of ALDH1A1 as a novel T-cell defined target suggests that its epitopes could potentially be useful as immunogens against tumors overexpressing ALDH1A1. The key role of this enzyme in several biochemical pathways implicated in carcinogenesis further heightens its relevance for SCCHN development.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA