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.
Cicinnati
Vito R
VR
Division of Basic Research, University of Pittsburgh Cancer Institute, Department of Pathology, Pittsburgh, PA 15213, USA.
Dworacki
Grzegorz
G
Albers
Andreas
A
Beckebaum
Susanne
S
Tüting
Thomas
T
Kaczmarek
Elzbieta
E
DeLeo
Albert B
AB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D019496:Cancer Vaccines; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology*; D013534:Survival; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
D019496:Cancer Vaccines; D016159:Tumor Suppressor Protein p53