Polyaromatic hydrocarbons are ubiquitous environmental compounds that are the major carcinogenic moiety in cigarette smoke and were present in the burning oilfield emissions in the Persian Gulf War. There has been intense experimental interest in identifying the mechanisms by which they cause cancer. It is now known that the polyaromatic hydrocarbon 7,12- dimethylbenz(a)anthracene (DMBA) produces a specific point mutation in 61st codon of the H- ras oncogene and that this mutation is necessary for tumors to develop. While it is clear that the tumors caused by carcinogenic polyaromatic hydrocarbons elicit a partially protective immune response, the role that T-cell mediated immunity plays at earlier stages in the cutaneous carcinogenesis pathway is not well-understood. Our studies funded through a VA Merit Review Award have shown that administration of DMBA to the skin of mice results in an antigen specific T-cell mediated immune response that confers resistance to DMBA-induced tumor development. The T-cell response is directed, at least in part, at the H-ras mutation in the 61st codon and an immune response to the endogenous non-mutated ras does not occur. Based on these findings, we hypothesize that vaccination strategies resulting T-cell mediated immunity to oncogene mutations produced by polyaromatic hydrocarbons serves to protect individuals against the carcinogenic effects of these agents, and efforts to amplify that response will further reduce the formation of polyaromatic hydrocarbon-induced cancers. To test our hypothesis, we have prepared a genetic-immunization vector containing a ubiquitin-mutant ras fusion minigene sequence which provides superior proteosome targeting of the encoded protein. This promotes MHC class I antigen processing and thereby enhances the generation of CD8+ T-cells. We have developed stable dendritic cell lines transfected with our vector, and intend to us them to vaccinate animals to establish whether they will prevent the DMBA-induced skin tumors. We will also evaluate the effect of dendritic cell vaccination with our vector on activation of T-cell subsets and on their cytokine profiles. Studies are planned to assess the effect of dendritic cell vaccination with mutant H-ras on the presence of H-ras mutations in tumors and in non-tumor-bearing DMBA treated skin. Finally, we will determine the role of IL-12 and IL-23 in the T-cell response to mutant H-ras and whether administration of these cytokines or their neutralization through antibody treatment will alter the efficacy of the vaccination procedure. The long-term goal of these studies is to identify methods for the immunoprevention of tumors caused by carcinogenic polyaromatic hydrocarbons. Veterans are likely to be among the major beneficiaries of such methods because of the high proportion of smokers in this population and because of their exposure to these agents during the Persian Gulf War.

Public Health Relevance

There is great interest in identifying the mechanisms by which chemicals cause cancer. This is especially true for polyaromatic hydrocarbons (PAHs), carcinogens that are present in cigarette smoke, charcoal broiled food, and were found in burning oilfields during the Persian Gulf War. PAHs are a major, if not the major, cancer producing agents among veterans. They cause lung cancer and have been implicated in cancers of the head and neck, bladder and breast. The skin is an important experimental model to define processes by which PAHs cause cancer, since it is easily accessible and tumors can be readily identified. Our studies suggest that there are important interactions between the immune system, PAHs and the mutations that PAHs produce. We have developed novel reagents and we utilize them as a vaccine to determine if they augment immunity to PAHs and can be used to prevent tumors from developing in the first place.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001059-02
Application #
8242611
Study Section
Oncology A (ONCA)
Project Start
2010-10-01
Project End
2014-09-30
Budget Start
2011-10-01
Budget End
2012-09-30
Support Year
2
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Birmingham VA Medical Center
Department
Type
DUNS #
082140880
City
Birmingham
State
AL
Country
United States
Zip Code
35233