Epigenetic Regulation of Ovarian Tumor Immunity.

摘要

The standard of care has produced marginal extension of remission rates in ovarian cancer. Based on preliminary observations that epigenetic regulators like Trichostatin A (TSA) can reduce ovarian tumor burden in a syngeneic murine model system, we tested the notion that TSA treatment leads to dendritic cell maturation that promotes effector CD8+ T cell over CD4+ T regulatory cell generation. At 10 mg/kg/day for 5 times on alternate days, TSA was able to control ovarian tumor growth, however the tumor growth resumed by day 40. Surprisingly, 1-MT; a known inhibitor of indole-amine 2,3-dioxygenase (IDO) was unable to cause ovarian tumor growth inhibition, which was attributed to its inability to block IDO expression in the ovarian tumor microenvironment. However, TSA mediated ovarian tumor control required MHC Class 1 dependent CD8+ T cells. These studies have identified the role of CD8+ T cells in promoting ovarian tumor immunity and delineated the ability of TSA mediated epigenetic alteration to enhance CD8+ T cell mediated ovarian tumor control. Ongoing studies are focused on testing new generation of IDO inhibitors for ovarian cancer.