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p53_110–124-specific Human CD4⁺ T-helper Cells Enhance in Vitro Generation and Antitumor Function of Tumor-reactive CD8⁺ T Cells¹

Division of Basic Research, University of Pittsburgh Cancer Institute and the Departments of Pathology [K. C., A. A., J. S., T. L. W., A. B. D.] and Otolaryngology [T. L. W.], School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Virginia Mason Research Institute and University of Washington School of Medicine, Seattle, Washington 98101 [W. W. K.] and National Cancer Institute, Bethesda, Maryland 20892 [E. A.]

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.

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