Immunogenicity of the carcinoembryonic antigen derived peptide 694 in HLA-A2 healthy donors and colorectal carcinoma patients.
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 CEA(694-702) 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 CEA(694-702) 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 CEA(694-702) 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.
Alves
Pedro M S
PM
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, HO-05, Rue Pierre-Decker, 4, 1005, Lausanne, Switzerland. Pedro.romero@isrec.unil.ch
Viatte
Sebastien
S
Fagerberg
Theres
T
Michielin
Olivier
O
Bricard
Gabriel
G
Bouzourene
Hanifa
H
Vuilleumier
Henri
H
Kruger
Thorsten
T
Givel
Jean-Claude
JC
Lévy
Frédéric
F
Speiser
Daniel E
DE
Cerottini
Jean-Charles
JC
Romero
Pedro
P
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002277:Carcinoma / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy*; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D011485:Protein Binding
D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments