Aryl Hydrocarbon (Dioxin) Receptor/Transcription Factor and Cytochrome P450 1B1 as Targets for Breast Cancer Immunotherapy.

摘要

Recent clinical successes have fostered renewed optimism among tumor immunologists. We exploited recent advances to identify immunogenic peptides from self proteins and to present those peptides to generate breast tumor- specific CD8+ killer T cell (CTL) in vitro. Two target proteins, the aryl hydrocarbon receptor/transcription factor (AhR) and the AhR-regulated cytochrome P45O CYPlBl enzyme, were selected for these studies because of their high level expression in breast tumors and their role in environmental chemical carcinogenesis. Three computer-based algorithms identified AhR- and CYPlBl peptides predicted to bind a common human HLA class 1 allele, HLA-A 020l. HLA stabilization experiments confirmed high affinity binding of several AhR and CYPlBl peptides to HLA-A O2Ol. Presentation of these peptides on activated B cells to autologous human CD8+ T cells in vitro induced CTL which lysed tumors expressing AhR or CYPlBl in an antigen- and HLA-class 1-specific manner CTL frequency analysis with fluorescent peptide/HLA-A(star)O2Ol tetramers indicated that l%-4% of the CD8+ T cell population generated in vitro was responsible for the killing activity Enrichment of the peptide/HLA-A(star)O2Ol-specific T cells significantly enriched the killing activity The data demonstrate the feasibility of developing breast cancer vaccines with a platform that combines bioinformatics and advanced strategies for tumor antigen presentation.