title: P53(110-124)-specific human CD4+ T-helper cells enhance in vitro generation and antitumor function of tumor-reactive CD8+ T cells.
abstract: 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.
authors.affiliation: Division of Basic Research, University of Pittsburgh Cancer Institute and the Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chikamatsu
authors.forename: Andreas
authors.initials: A
authors.lastname: Albers
authors.forename: Joanna
authors.initials: J
authors.lastname: Stanson
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Albert B
authors.initials: AB
authors.lastname: DeLeo
mesh_terms: D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002294:Carcinoma, Squamous Cell; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D009062:Mouth Neoplasms; D010446:Peptide Fragments / Q000494:pharmacology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology*
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma