The humoral immune response to the p53 tumor suppressor antigen and its relatives, p73 and p63

Professor Thierry Soussi, PhD

Laboratoire de génotoxicologie des tumeurs, Institut Curie, Université P.M. Curie, Paris, France.

p53 antibodies (p53-Abs) were discovered 20 years ago during the course of Tumor Associated Antigens screening. The discovery of p53 mutations and accumulation of p53 in human tumors shed new light on the p53 humoral response. p53-Abs are found predominantly in human cancer patients with a specificity of 96%. Such antibodies are predominantly associated with p53 gene missense mutations and p53 accumulation in the tumor, but the sensitivity of such detection is only 30%. It has been demonstrated that this immune response is due to a self immunization process linked to the strong immunogenicity of the p53 protein. p53-Abs are associated with high-grade tumors and poor survival in breast, colon, oral and gastric cancers. The finding of p53 antibodies in the sera of individuals who are at high risk of cancer, such as exposed workers or heavy smokers, indicates that they have promising potential in the early detection of cancer. Studies of the epitope recognized by these p53-Abs indicates that they bind both wild-type and mutant p53. Using either truncated p53 or synthetic peptides, it has been demonstrated that the epitopes recognized by the p53-Abs are mainly located in the amino and carboxy terminal regions of the protein, regions which are not in the hot spot areas for the p53 mutation. These immunodominant epitopes have also been detected in the sera of mice and rabbits hyperimmunized with wild-type p53. Taken together, i) the presence of immunodominant epitopes outside the hot spot region of the p53 mutation, ii) the correlation between p53 accumulation (and p53 gene mutation) in tumor cells and p53 antibody responses, iii) the similarity of humoral responses in patients independent of the cancer type and iv) the similarity of antigenic site profiles in patients and hyperimmunized animals all suggest that p53 accumulation is a major component of the humoral response in patients with cancer. This accumulation could lead to a self immunization process culminating in the appearance of p53 antibodies. The level of p53 proteins in a normal organism is very low, suggesting very weak (if any) tolerance to endogenous p53 The recent discovery of two new member of the p53 family, p73 and p63, led to the study of the specificity of this immune response toward the three proteins. Serum samples from patients with various types of cancer were tested for antibodies against p73 and p63 using immunoprecipitation. Seventy-two patients were previously shown to have p53 antibodies whereas 76 were negative. The control group consisted of 50 blood donors. p73 antibodies were detected in 14.9% of the cancer patients, (11/72 in the group with p53-antibodies and 11/76 in the negative group). Only two sera from the control (4%) were positive. p63 antibodies were detected in only 4/148 (2.7%) of the cancer patient. Epitope mappings were performed and demonstrate that p73 antibodies are directed toward the central region. Our results indicates that there is a specific immune response toward the p73 protein in cancer patients, a finding supported by an increasing number of publication describing p73 accumulation in tumoral cell.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Basis of Oncogenesis.