Abstract
215
Induction of tumor-specific immune responses results in the inhibition of tumor development. However, tumor recurs because of the tumor immunoediting process that facilitates development of escape mechanisms in tumors. It is not known whether tumor escape is an active process whereby anti-tumor immune responses induce loss or downregulation of the target antigen in the antigen positive clones. To address this question, we used rat neu-overexpressing Mouse Mammary Carcinoma (MMC) and its relapsed neu Antigen Negative Variant (ANV). ANV emerged from MMC under pressure from the neu-specific T cell responses, in vivo. Since initial rejection of MMC was associated with the presence of IFN-γ secreting T cells, we treated MMC with IFN-γ to determine whether it may downregulate the expression of neu antigen in MMC. Using bisulfite genomic sequencing we found that IFN-γ induced methylation of the neu promoter resulting in downregulation of neu expression. In vivo studies also confirmed that IFN-γ receptor positive MMC were more likely to relapse when compared to IFN-γ receptor negative MMC. Together, these data suggest that neu antigen loss is an active process which occurs in primary tumors due to the neu-targeted anti-tumor immune responses.
This work was supported by the NIH R01 CA104757 (MHM) and the Susan G. Komen Grant BCTR0504184.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA