title: Identification of human aldehyde dehydrogenase 1 family member A1 as a novel CD8+ T-cell-defined tumor antigen in squamous cell carcinoma of the head and neck.
abstract: Few epitopes are available for vaccination therapy of patients with squamous cell carcinoma of the head and neck (SCCHN). Using a tumor-specific CTL, aldehyde dehydrogenase 1 family member A1 (ALDH1A1) was identified as a novel tumor antigen in SCCHN. Mass spectral analysis of peptides in tumor-derived lysates was used to determine that the CTL line recognized the HLA-A*0201 (HLA-A2) binding ALDH1A1(88-96) peptide. Expression of ALDH1A1 in established SCCHN cell lines, normal mucosa, and primary keratinocytes was studied by quantitative reverse transcription-PCR and immunostaining. Protein expression was further defined by immunoblot analysis, whereas ALDH1A1 activity was measured using ALDEFLUOR. ALDH1A1(88-96) peptide was identified as an HLA-A2-restricted, naturally presented, CD8(+) T-cell-defined tumor peptide. ALDH1A1(88-96) peptide-specific CD8(+) T cells recognized only HLA-A2(+) SCCHN cell lines, which overexpressed ALDH1A1, as well as targets transfected with ALDH1A1 cDNA. Target recognition was blocked by anti-HLA class I and anti-HLA-A2 antibodies. SCCHN cell lines overexpressing ALDH1 had high enzymatic activity. ALDH1A1 protein was expressed in 12 of 17 SCCHN, and 30 of 40 dysplastic mucosa samples, but not in normal mucosa. ALDH1A1 expression levels in target cells correlated with their recognition by ALDH1A1(88-96) peptide-specific CD8(+) T cells. Our findings identify ALDH1A1, a metabolic antigen, as a potential target for vaccination therapy in the cohort of SCCHN subjects with tumors overexpressing this protein. A smaller cohort of subjects with SCCHN, whose tumors express little to no ALDH1A1, and thus are deficient in conversion of retinal to retinoic acid, could benefit from chemoprevention therapy.
authors.affiliation: Division of Basic Research, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Visus
authors.forename: Diasuke
authors.initials: D
authors.lastname: Ito
authors.forename: Andrew
authors.initials: A
authors.lastname: Amoscato
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Maciejewska-Franczak
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdelsalem
authors.forename: Rajiv
authors.initials: R
authors.lastname: Dhir
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Vera S
authors.initials: VS
authors.lastname: Donnenberg
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Albert B
authors.initials: AB
authors.lastname: DeLeo
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D000080924:Aldehyde Dehydrogenase 1 Family; D000951:Antigens, Neoplasm / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology*; D045744:Cell Line, Tumor; D015789:HLA-A2 Antigen / Q000276:immunology; D006258:Head and Neck Neoplasms / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D010446:Peptide Fragments / Q000032:analysis* / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D050697:Retinal Dehydrogenase
chemical_list: D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D012333:RNA, Messenger; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase