Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

✍ Scribed by Peter A. Würtzen; Lars Ø. Pedersen; Hans S. Poulsen; Mogens H. Claesson

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: French
• Weight: 144 KB
• Volume: 93
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.1417

✦ Synopsis

p53 is upregulated in the majority of spontaneous tumors and the HLA class I molecule HLA-A2 is expressed by approximately 50% of the caucasians. Potentially, these facts make HLA-A2-binding p53 peptides for CTL-inducing immunotherapy applicable to a broad range of cancer patients. In our study, we investigated the CTL-inducing capacity of autologous monocyte-derived dendritic cells (DC) maturated by exposure to CD40L and pulsed with a pool of 4 wild-type, HLA-A2-binding p53 peptides, and the p53-specific CD8 ؉ CTL lines established from healthy HLA-A2-positive donors were characterized. Reactivity to p53 65-73 and p53 187-197 peptides was obtained in the T-cell lines. Interestingly, cold target inhibition experiments demonstrated that the simultaneous recognition of the 2 peptides was the result of crossreactivity, which was confirmed by killing experiments at the clonal CTL level. Furthermore, 4 HLA-A2 ؉ p53-mutated tumor cell lines were lysed by the CTL line, indicating that these peptides are endogenously processed and presented on HLA-A2 molecule. Thus, monocyte-derived DC pulsed with a pool of peptides are able to induce CTL reactivity to wildtype p53 peptides presented by several cancer cell lines. In addition, the recognition of 2 different p53 peptides by the same CTL clone suggests a promiscuous peptide recognition by the TCR involved. Taken together, these in vitro results suggest that vaccination with autologous DC pulsed with multiple p53 epitopes may induce an effective tumor-specific CTL response in vivo with the potential to eradicate p53upregulated spontaneously occurring tumors.