P53(110-124)-specific human CD4+ T-helper cells enhance in vitro generation and antitumor function of tumor-reactive CD8+ T cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-07, Vol.63 (13), p.3675-3681
• Main Authors: Chikamatsu, Kazuaki, Albers, Andreas, Stanson, Joanna, Kwok, William W, Appella, Ettore, Whiteside, Theresa L, DeLeo, Albert B
• Format: Article
• Language: English
• Subjects: Carcinoma, Squamous Cell; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; HLA-DR Antigens - immunology; HLA-DRB1 Chains; Humans; Interferon-gamma - analysis; Mouth Neoplasms; Peptide Fragments - pharmacology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - pharmacology
• ISSN: 0008-5472

Current evidence suggests that the optimal vaccines for cancer should incorporate tumor-specific cytotoxic as well as helper epitopes. Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines, which could combine multiple tumor epitopes defined by CD8(+) CTLs, as well as CD4(+) T-helper cells. To test this possibility, we generated anti-p53 CD4(+) T cells from peripheral blood obtained from an HLA-DRB1*0401(+) donor by in vitro stimulation with dendritic cells and recombinant human p53 protein. We identified the wt p53(110-124) peptide as a naturally presented epitope. In a series of ex vivo experiments, performed in an autologous human system, we then demonstrated the ability of anti-wt p53(110-124) CD4(+) T cells to enhance the generation and antitumor functions of CD8(+) effector cells. The results demonstrate the crucial role of T helper-defined epitopes in shaping the immune response to multiepitope cancer vaccines targeting p53. This model of tumor-specific CD8(+) and CD4(+) T-cell interactions suggests that future vaccination strategies targeting tumor cells should incorporate helper and cytotoxic T cell-defined epitopes.