Self-Tolerance Does Not Restrict the CD4+ T-Helper Response against the p53 Tumor Antigen

• Published in: Cancer research (Chicago, Ill.) Ill.), 2008-02, Vol.68 (3), p.893-900
• Main Authors: LAUWEN, Marjolein M, ZWAVELING, Sander, DE QUARTEL, Linda, FERREIRA MOTA, S. Carmela, GRASHORN, Janine A. C, MELIEF, Cornelis J. M, VAN DER BURG, Sjoerd H, OFFRINGA, Rienk
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibody Affinity; Antigen Presentation; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - immunology; Cross Reactions; Epitopes, T-Lymphocyte; Female; Immunotherapy, Adoptive; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; Pharmacology. Drug treatments; Self Tolerance - immunology; T-Lymphocytes, Helper-Inducer - immunology; Tumor Suppressor Protein p53 - immunology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-3166

Tumorigenesis is frequently associated with mutation and overexpression of p53, which makes it an attractive target antigen for T cell-mediated immunotherapy of cancer. However, the magnitude and breadth of the p53-specific T-cell repertoire may be restricted due to the ubiquitous expression of wild-type p53 in normal somatic tissues. In view of the importance of the CD4+ T-helper cell responses in effective antitumor immunity, we have analyzed and compared the p53-specific reactivity of this T cell subset in p53+/+ and p53-/- C57Bl/6 mice. This response was found to be directed against the same three immunodominant epitopes in both mouse types. Fine-specificity, magnitude, and avidity were not affected by self-tolerance. Immunization of p53-/- and p53+/+ mice with synthetic peptide vaccines comprising the identified epitopes induced equal levels of Th1 immunity. Our findings imply that the p53-specific CD4+ T-cell repertoire is not restricted by self-tolerance and is fully available for the targeting of cancer.