Immunoprevention of Chemical Carcinogenesis through Early Recognition of Oncogene Mutations

Abstract

Prevention of tumors induced by environmental carcinogens has not been achieved. Skin tumors produced by polyaromatic hydrocarbons, such as 7,12-dimethylbenzanthracene (DMBA) often harbor an H-ras point mutation, suggesting that it is a poor target for early immune surveillance. The application of pyrosequencing and allele-specific PCR techniques established that mutations in the genome and expression of the Mut H-ras gene could be detected as early as one day after DMBA application. Further, DMBA sensitization raised Mut H-ras epitope-specific CTLs capable of eliminating Mut H-ras+ pre-neoplastic skin cells, demonstrating that immunosurveillance is normally induced but may be ineffective due to insufficient effector pool size and/or immune suppression. To test whether selective pre-expansion of CD8 T cells with specificity for the single Mut H-ras epitope was sufficient for tumor prevention, MHC class I-epitope-focused lentivector-infected dendritic cell (DC)- and DNA-based vaccines were designed to bias toward CTL rather than Treg induction. Mut H-ras but not wild-type H-ras epitope-focused vaccination generated specific CTL and inhibited DMBA-induced tumor initiation, growth and progression in preventative and therapeutic settings. Transferred Mut H-ras-specific effectors induced rapid tumor regression, overcoming established tumor suppression in tumor bearing mice. These studies support further evaluation of oncogenic mutations for their potential to act as early tumor-specific, immunogenic epitopes to expand relavent immunesurviellance effectors in order to block tumor formation, rather than treating established tumors.

Cancer immunoprevention

“…In another recent report, vaccination against the Epidermal Growth Factor Receptor (EGFR) using a multipeptide vaccine in a preventive setting decreased EGFR-driven lung carcinogenesis by 76.4% in a mouse model of EGFR-driven lung cancer, by inducing robust immunity. Of a particular interest is a recent study that showed that immunizing against the common mutation in H-ras oncogene can prevent chemical carcinogen-induced tumors that are known to carry that mutation [32]. Thus identification of common oncogene mutations in premalignant lesions could provide mutated epitopes against which a very safe and likely very strong immune response could be generated with a vaccine.…”

IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations

“…We employed allergic contact hypersensitivity (CHS) assays to measure T cell-mediated CHS responses to DMBA, the compound responsible for nevus development in this system. Recent work from our lab has shown that a significant portion of DMBA-specific T cells is raised to an epitope containing the codon 61 point mutation that activates H-ras (17). CHS responses were exaggerated in IL-12p35KO mice, but were significantly reduced in IL-23p19KO mice ( Fig.…”

“…Elicitation of responses was assessed 5 days after sensitization by painting ears with DMBA (20 μl; 0.1% w/v DMBA in acetone) as described (17). To assess the extent of suppression by DMBA specific regulatory T cells, mice were sensitized as described above.…”

Transcriptome profiling in oral cavity and esophagus tissues from (S)‐N′‐nitrosonornicotine‐treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis

“…Recent studies in several cancer models consistently indicate that an immunosuppressive environment is established early in tumor development to effectively thwart the immune response to neoplastic cells . Therefore, immune‐prevention is now considered as a strategy to prevent cancer through the use of vaccines, antibodies, and immune modulators .…”