Impact of p53‐based immunization on primary chemically‐induced tumors

In mice as well as humans, cytotoxic T lymphocytes (CTL) specific for wild‐type‐sequence (wt) p53 peptides have been shown to react against a wide range of tumors, but not normal cells. As such, they are attractive candidates for developing broadly applicable cancer vaccines. Of particular interest is the potential of using p53‐based vaccines in high‐risk individuals to prevent cancer. Methylcholanthrene, an immunosuppressive polycyclic hydrocarbon carcinogen implicated as a causative agent in human cancers, has long been used to induce murine tumors with a high incidence of genetic alterations and sensitivity to wt p53‐specific CTL. To analyze the potential of p53‐based vaccines on primary tumors, we evaluated the efficacy of DNA and dendritic cell vaccines targeting wt p53 peptides given to methylcholanthrene‐treated mice in the protection or therapy settings. The results indicate that the efficacy of these vaccines relative to reducing tumor incidence were severely compromised by vaccine‐induced tumor escape. As compared to tumors induced in non‐immunized mice, a higher incidence of epitope‐loss tumors was detected in tumors from the immunized mice. The increase in tumor escape arose as a consequence of either increased frequencies of mutations within/flanking p53 epitope‐coding regions or downregulation of expression of the major histocompatibility complex Class I molecules that present these epitopes for T cell recognition These findings are consistent with current views of immunoselection occurring in patients receiving tumor peptide‐based immunotherapy, and impact on the design and implementation of p53‐based vaccines, in particular, those aimed at treating individuals at high risk for developing cancer. © 2004 Wiley‐Liss, Inc.