Cancer Immunology, Immunotherapy

, Volume 56, Issue 11, pp 1795–1805 | Cite as

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

  • Pedro M. S. Alves
  • Sebastien Viatte
  • Theres Fagerberg
  • Olivier Michielin
  • Gabriel Bricard
  • Hanifa Bouzourene
  • Henri Vuilleumier
  • Thorsten Kruger
  • Jean-Claude Givel
  • Frédéric Lévy
  • Daniel E. Speiser
  • Jean-Charles Cerottini
  • Pedro Romero
Original Article

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 

Abbreviations

h

Hour

HLA-A2

HLA-*0201

mAb

Monoclonal antibody

MFI

Mean fluorescence intensity

n.d.

Not done

PCR

Polymerase chain reaction

Notes

Acknowledgments

This study was supported in part by Swiss National Science Foundation special program NCCR Molecular Oncology. We would like to acknowledge the technical support of Estelle Devevre and Frederic Grosjean and Nicole Montandon.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Pedro M. S. Alves
    • 1
    • 2
    • 3
  • Sebastien Viatte
    • 2
    • 3
  • Theres Fagerberg
    • 2
    • 6
  • Olivier Michielin
    • 2
    • 6
    • 7
  • Gabriel Bricard
    • 1
  • Hanifa Bouzourene
    • 4
  • Henri Vuilleumier
    • 5
  • Thorsten Kruger
    • 5
  • Jean-Claude Givel
    • 5
  • Frédéric Lévy
    • 2
  • Daniel E. Speiser
    • 1
  • Jean-Charles Cerottini
    • 2
  • Pedro Romero
    • 1
  1. 1.Division of Clinical Onco-ImmunologyLudwig Institute for Cancer Research, Hôpital Orthopédique, HO-05LausanneSwitzerland
  2. 2.Ludwig Institute for Cancer Research, Lausanne BranchUniversity of LausanneEpalingesSwitzerland
  3. 3.Molecular OncologyNational Center for Competence in Research (NCCR)LausanneSwitzerland
  4. 4.Institut Universitaire de PathologieCentre Hospitalier Universitaire VaudoisLausanneSwitzerland
  5. 5.Department of SurgeryCentre Hospitalier Universitaire VaudoisLausanneSwitzerland
  6. 6.Swiss Institute of BioInformaticsBaselSwitzerland
  7. 7.Multidisciplinary Oncology CenterLausanne University HospitalLausanneSwitzerland

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