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Identification of a novel epitope derived from the cancer-germline antigen, HAGE, displaying both in-vitro and in-vivo immunogenicity

  • Ashley Knights
  • Stephanie McArdle
  • Ludmila Müller
  • Robert Rees
  • Graham Pawelec
Open Access
Poster presentation
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Keywords

Tumour Antigen Acute Myeloid Leukaemia Immunogenic Peptide Current Tumour Specific Cytotoxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

It is now well established that both CD4+ and CD8+ tumour-specific T-lymphocytes play critical roles in anti-tumour immunity; thus there is a desirability to identify both MHC class I and II-restricted tumour antigens that induce immunogenic responses in both in-vitro models and more significantly in an in-vivo environment. Many current tumour antigens that are potential targets fall into the category of cancer-germline (CG) antigens, and are considered to represent good candidate antigens for tumour immunotherapy based on their lack of expression on normal somatic tissues. HAGE is a novel CG gene expressed in a wide range of solid tumour tissue (eg. around 20% of melanomas, one-third of lung cancers) but also in haematological malignancies (in >50% and >20% of chronic and acute myeloid leukaemias, respectively). Here we describe the use of a combination of computer algorithms to identify potentially immunogenic peptides from the HAGE protein based on both predicted HLA affinity and proteosomal cleavage sites. An HLA-A2-binding motif contained within a longer HLA-DR-binding sequence was identified. Two peptides representing either the class I motif alone, or a longer peptide containing the class I motif within the class II motif, were then screened in in-vitro T cell sensitisation experiments using PBMC or monocyte-derived dendritic cells from healthy donors or CML patients; the class I peptide was also used in-vivo to vaccinate HLA-A2-transfected mice. We demonstrate that both these peptides are immunogenic in-vitro not only for T cells from healthy donors, but also from CML patients, as assessed by functional assays such as cytokine secretion and cytotoxicity. Moreover, immunogenicity was confirmed by using MHC/peptide tetramers to show specific expansion of sensitised T-cells. Furthermore, the class I peptide also demonstrates immuno-genicity in-vivo following vaccination of HLA-A2-transfected mice. Spleen cells isolated from these mice showed specific cytotoxicity ex-vivo. We conclude that the HLA-DR-binding peptide and the HLA-A2 motif contained therein may represent potential vaccines for the immunotherapeutic treatment of cancer, particularly CML, targeting the HAGE expression of a high proportion of tumours.

Copyright information

© Author(s); licensee BioMed Central Ltd. 2004

Authors and Affiliations

  • Ashley Knights
    • 1
  • Stephanie McArdle
    • 2
  • Ludmila Müller
    • 1
  • Robert Rees
    • 2
  • Graham Pawelec
    • 1
  1. 1.Section for Transplantation Immunology and ImmunohaematologyUniversitätsklinikum Tübingen, ZMFTübingenGermany
  2. 2.Department of Life ScienceNottingham Trent UniversityNottinghamUK

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