Identification of a broad coverage HLA-DR degenerate epitope pool derived from carcinoembryonic antigen

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2010-01, Vol.59 (1), p.161-171
• Main Authors: Karyampudi, Lavakumar, Krco, Christopher J, Kalli, Kimberly R, Erskine, Courtney L, Hartmann, Lynn C, Goodman, Karin, Ingle, James N, Maurer, Matthew J, Nassar, Aziza, Yu, Chao, Disis, Mary L, Wettstein, Peter J, Fikes, John D, Beebe, Melanie, Ishioka, Glenn, Knutson, Keith L
• Format: Article
• Language: English
• Subjects: Adult; Antigens; Antineoplastic agents; Biological and medical sciences; Breast cancer; Breast Neoplasms - immunology; Cancer Research; Carcinoembryonic Antigen - immunology; CD4-Positive T-Lymphocytes - immunology; Cells; Clinical trials; Epitopes; Female; HLA-DR Antigens - immunology; Humans; Immunology; Immunotherapy; Lymphocytes; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original Article; Ovarian cancer; Ovarian Neoplasms - immunology; Peptides; Pharmacology. Drug treatments; Proteins; Software; Vaccines
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-009-0738-z

CD4 T cells are important for anti-tumor immune responses. Aside from their role in the activation of CD8 T cells, CD4 T cells also mediate anti-tumor immune responses by recruiting innate immune effectors into the tumor microenvironment. Thus, the search for strategies to boost CD4 T cell immunity is an active area of research. Our goal in this study was to identify HLA-DR epitopes of carcinoembryonic antigen (CEA), a commonly over-expressed tumor antigen. HLA-DR epitopes of CEA were identified using the epitope prediction program, PIC (predicted IC₅₀) and tested using in vitro HLA-DR binding assays. Following CEA epitope confirmation, IFN-γ ELIspot assays were used to detect existing immunity against the HLA-DR epitope panel of CEA in breast and ovarian cancer patients. In vitro generated peptide-specific CD4 T cells were used to determine whether the epitopes are naturally processed from CEA protein. Forty-three epitopes of CEA were predicted, 15 of which had high binding affinity for 8 or more common HLA-DR molecules. A degenerate pool of four, HLA-DR restricted 15 amino acid epitopes (CEA.24, CEA.176/354, CEA.488, and CEA.653) consisting of two novel epitopes (CEA.24 and CEA.488) was identified against which 40% of breast and ovarian cancer patients had pre-existent T cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in ~94% of patients. Patients with breast or ovarian cancer demonstrate pre-existent immune responses to the tumor antigen CEA. The degenerate pool of CEA peptides may be useful for augmenting CD4 T cell immunity.