HLA-A*0201-restricted CEA-derived Peptide CAP1 Is Not a Suitable Target for T-cell-based Immunotherapy

Carcinoembryonic antigen (CEA) is a potential target for antigen-specific immunotherapy, as it is frequently over-expressed in human carcinomas. Moreover, an epitope derived from CEA, designated CAP1 (YLSGANLNL), has been proposed as naturally processed and presented by tumors in the human leukocyte antigen (HLA)-A*0201 context. Our aim was to fully characterize and assess the clinical relevance of the HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) response against CEA. Stable and potent artificial antigen presenting cells (AAPCs) were used to evaluate T-cell response against CEA. These cells efficiently activate CTLs against tumor-derived epitopes after transduction with the antigenic peptides or full-length proteins. We found that AAPCs genetically modified to express CAP1, the agonist peptide CAP1-6D, or the whole CEA protein were not able to activate CAP1-specific CTLs from HLA-A*0201(+) healthy donors or patients with colorectal carcinoma, even after multiple stimulations. In addition, we showed that a CAP1-specific T-cell clone, obtained after multiple stimulations of T cells of a HLA-A*0201(+) healthy donor in vitro with autologous antigen presenting cells, recognized CEA(-) HLA-A*0201(+) tumors transduced with a minigene encoding CAP1 but failed to react against HLA-A*0201(+) tumor cells expressing CEA. Finally, AAPCs expressing the whole CEA protein did not induce any specific CTL response against CEA(+) HLA-A*0201(+) tumor cells highlighting the potential difficulty of mounting an efficacious T-cell response against this autoantigen. Altogether, our data indicate that CAP1 is not efficiently processed and presented by CEA(+) tumor cells, and therefore, is not an appropriate target for T-cell-based immunotherapy.