title: ADAM metallopeptidase domain 17 (ADAM17) is naturally processed through major histocompatibility complex (MHC) class I molecules and is a potential immunotherapeutic target in breast, ovarian and prostate cancers.
abstract: Selection of suitable antigens is critical for the development of cancer vaccines. Most desirable are over-expressed cell surface proteins that may serve as targets for both antibodies and T cells, thus maximizing a concerted immune response. Towards this goal, we characterized the relevance of tumour necrosis factor-α-converting enzyme (ADAM17) for such targeted therapeutics. ADAM17 is one of the several metalloproteinases that play a key role in epidermal growth factor receptor (EGFR) signalling and has recently emerged as a new therapeutic target in several tumour types. In the present study, we analysed the expression profile of ADAM17 in a variety of normal and cancer cells of human origin and found that this protein is over-expressed on the surface of several types of cancer cells compared to the normal counterparts. Furthermore, we analysed the presentation of a human leucocyte antigen (HLA)-A2-restricted epitope from ADAM17 protein to specific T cells established from normal donors as well as ovarian cancer patients. Our analysis revealed that the HLA-A2-restricted epitope is processed efficiently and presented by various cancer cells and not by normal cells. Tumour-specific T cell activation results in the secretion of both interferon-γ and granzyme B that can be blocked by HLA-A2 specific antibodies. Collectively, our data present evidence that ADAM17 can be a potential target antigen to devise novel immunotherapeutic strategies against ovarian, breast and prostate cancer.
authors.affiliation: Immunotope, Inc., The Pennsylvania Biotechnology Center, Doylestown, PA 18902, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sinnathamby
authors.forename: J
authors.initials: J
authors.lastname: Zerfass
authors.forename: J
authors.initials: J
authors.lastname: Hafner
authors.forename: P
authors.initials: P
authors.lastname: Block
authors.forename: Z
authors.initials: Z
authors.lastname: Nickens
authors.forename: A
authors.initials: A
authors.lastname: Hobeika
authors.forename: A A
authors.initials: AA
authors.lastname: Secord
authors.forename: H K
authors.initials: HK
authors.lastname: Lyerly
authors.forename: M A
authors.initials: MA
authors.lastname: Morse
authors.forename: R
authors.initials: R
authors.lastname: Philip
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000072198:ADAM17 Protein; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D053804:Granzymes / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D010446:Peptide Fragments; D007371:Interferon-gamma; D053804:Granzymes; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human