Original Article

Cancer Immunology, Immunotherapy

, Volume 56, Issue 11, pp 1795-1805

First online:

Immunogenicity of the carcinoembryonic antigen derived peptide 694 in HLA-A2 healthy donors and colorectal carcinoma patients

  • Pedro M. S. AlvesAffiliated withDivision of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, HO-05Ludwig Institute for Cancer Research, Lausanne Branch, University of LausanneMolecular Oncology, National Center for Competence in Research (NCCR)
  • , Sebastien ViatteAffiliated withLudwig Institute for Cancer Research, Lausanne Branch, University of LausanneMolecular Oncology, National Center for Competence in Research (NCCR)
  • , Theres FagerbergAffiliated withLudwig Institute for Cancer Research, Lausanne Branch, University of LausanneSwiss Institute of BioInformatics
  • , Olivier MichielinAffiliated withLudwig Institute for Cancer Research, Lausanne Branch, University of LausanneSwiss Institute of BioInformaticsMultidisciplinary Oncology Center, Lausanne University Hospital
  • , Gabriel BricardAffiliated withDivision of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, HO-05
  • , Hanifa BouzoureneAffiliated withInstitut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois
  • , Henri VuilleumierAffiliated withDepartment of Surgery, Centre Hospitalier Universitaire Vaudois
  • , Thorsten KrugerAffiliated withDepartment of Surgery, Centre Hospitalier Universitaire Vaudois
  • , Jean-Claude GivelAffiliated withDepartment of Surgery, Centre Hospitalier Universitaire Vaudois
    • , Frédéric LévyAffiliated withLudwig Institute for Cancer Research, Lausanne Branch, University of Lausanne
    • , Daniel E. SpeiserAffiliated withDivision of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, HO-05
    • , Jean-Charles CerottiniAffiliated withLudwig Institute for Cancer Research, Lausanne Branch, University of Lausanne
    • , Pedro RomeroAffiliated withDivision of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, HO-05 Email author 

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Abstract

Carcinoembryonic antigen (CEACAM5) is commonly overexpressed in human colon cancer. Several antigenic peptides recognized by cytolytic CD8+ T-cells have been identified and used in colon cancer phase-I vaccination clinical trials. The HLA-A*0201-binding CEA694–702 peptide was recently isolated from acid eluted MHC-I associated peptides from a human colon tumor cell line. However, the immunogenicity of this peptide in humans remains unknown. We found that the peptide CEA694–702 binds weakly to HLA-A*0201 molecules and is ineffective at inducing specific CD8+ T-cell responses in healthy donors. Immunogenic-altered peptide ligands with increased affinity for HLA-A*0201 were identified. Importantly, the elicited cytolytic T lymphocyte (CTL) lines and clones cross-reacted with the wild-type CEA694–702 peptide. Tumor cells expressing CEA were recognized in a peptide and HLA-A*0201 restricted fashion, but high-CEA expression levels appear to be required for CTL recognition. Finally, CEA-specific T-cell precursors could be readily expanded by in vitro stimulation of peripheral blood mononuclear cell (PBMC) from colon cancer patients with altered CEA peptide. However, the CEA-specific CD8+ T-cell clones derived from cancer patients revealed low-functional avidity and impaired tumor-cell recognition. Together, using T-cells to demonstrate the processing and presentation of the peptide CEA694-702, we were able to corroborate its presentation by tumor cells. However, the low avidity of the specific CTLs generated from cancer patients as well as the high-antigen expression levels required for CTL recognition pose serious concerns for the use of CEA694-702 in cancer immunotherapy.

Keywords

CTL Tumor immunology Cancer vaccines Tetramers