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CD4⁺ T Cells from Healthy Subjects and Colon Cancer Patients Recognize a Carcinoembryonic Antigen-specific Immunodominant Epitope

¹ Experimental Immunology Unit,
² Laboratory of Tumor Immunology, and
³ Cancer Immunotherapy and Gene Therapy Program, Department of Biology and Technology, Scientific Institute H. San Raffaele, 20132 Milan, Italy;
⁴ Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55108; and
⁵ Consiglio Nazionale delle Ricerche-Istituto di Chimica del Riconoscimento Molecolare, 20131 Milan, Italy

The carcinoembryonic antigen (CEA) is an attractive target for immunotherapeutic purposes because of its expression profile, its role in tumor progression, and its immunogenicity. However, CEA belongs to the CD66 immunoglobulin super-gene family that comprises highly homologous molecules expressed on leukocytes, making CEA a potential autoantigen expressed on hematopoietic cells. We used a MHC class II epitope prediction algorithm (TEPITOPE) to select 11 sequence segments of CEA that could form promiscuous CD4⁺ T-cell epitopes and used synthetic peptides corresponding to the predicted sequences to propagate in vitro CD4⁺ T cells from healthy donors and colon cancer patients. CD4⁺ T cells from all subjects strongly recognized the sequence segment (LWWVNNQSLPVSP), repeated at residues 177–189 and 355–367. Importantly, we demonstrated that this highly immunodominant region contains a naturally processed epitope(s). Cross-recognition experiments with peptide analogues present on the CD66 homologous proteins showed that CEA_{177–189/355–367}-specific CD4⁺ T cells did not recognize the analogues, demonstrating that recognition of the immunodominant epitope is CEA specific. These data suggest that the repertoire of CEA_{177–189/355–367}-specific CD4⁺ T cells might have been shaped by a selective process to exclude CD4⁺ T cells specific for CD66 homologues expressed on leukocyte, while preserving the CEA-specific repertoire. The features of strong immunogenicity and immunodominance in the absence of potential induction of autoimmunity make the identified CEA epitope of particular interest for the development of antitumor vaccines.

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