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

Abstract

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.Key words: methylcholanthrene; mouse sarcomas; p53; vaccine; immune evasionThe immunotherapeutic targeting of p53 is a particularly active area of investigation. p53 was initially identified as a transformation-related antigen expressed at elevated levels in chemically induced sarcomas and other transformed cells of the mouse. 1 Its subsequent classification as a tumor suppressor gene product that is genetically altered frequently in human tumors 2,3 made it an attractive candidate for development of cancer vaccines. The most common type of genetic alteration in p53 involves a missense mutation. Although these mutations represent ideal targets for tumor specific vaccines, the constraints imposed by antigen presentation limit their use. 4 Frequent accumulation of mutant p53 molecules in tumors, however, suggested that enhanced presentation by these tumors of wild-type sequence (wt) epitopes derived from these molecules for T cell recognition might occur 5 Like most of the presently defined melanoma antigens, wt p53 epitopes can be considered as widely expressed tumor associated antigens, 6 and vaccines targeting them would have broad applicability. [7][8][9] The potential of using p53-based vaccines in high-risk individuals to prevent cancer is of particular interest.Accompanying the...

Targeting cancer stem cells with p53 modulators

“…As for treatment with the single epitope p53 V1 vaccine, its lack of efficacy was also noted in our previous study and was attributed to immunoselection and the outgrowth of vaccine-induced epitope loss tumors [36]. The tumors either expressed mutations within the targeted p53 peptide epitope or have undergone a loss of H-2K b expression, which abrogated the ability of T-cell effectors to target these tumors [36].…”

“…Therefore, a preventative/therapeutic approach to target p53 by combining p53 SMWC together with a p53 peptide-pulsed, dendritic cell (DC)-based vaccine in a methylcholanthrene (MCA) - induced primary murine tumor model was investigated. In a previous study involving the MCA tumor model, immunotherapy with the single epitope p53 158-166 peptide-based vaccine, p53 V1, was found to have limited efficacy due to vaccine-induced immunoselection of epitope loss variants and tumor escape [36]. Here, we posit that a p53 peptide-based vaccine combined with p53 SMWC would prove to be more effective than either modality alone for the prevention/therapy of tumors in MCA mice.…”

Inhibition of Soluble Tumor Necrosis Factor Prevents Chemically Induced Carcinogenesis in Mice

“…MCA-induced cancers are immunogenic (24). Therefore, sTNF exclusion-induced increased resistance to MCA-induced carcinogenesis could be caused by a modified and/or enhanced anti-tumor immune response.…”

Immunologic aspect of ovarian cancer and p53 as tumor antigen

“…Cicinnati et al studied the potential of prophylactic vaccination with p53 epitopes using DNA and /or peptide pulsed dendritic cell vaccination in the tumor model giving rise to sarcomas[105]. Compared to control mice a higher incidence of epitope loss tumors were detected in the prophylactic vaccinated group resulting in an increase in tumor growth.…”