CONNECTIVITY MAP-BASED NEW DISCOVERY OF VORINOSTAT TO ENHANCE THE PROLIFERATION AND ANTI -TUMOR ACTIVITY OF NK CELLS

초록

Background & Aim NK cells are components of the innate immune cells that have a potent cytolytic activity against tumors. Various strategies have been explored to increase the number of NK cells and their anti-tumor function. However, little is known about the successful approaches applying FDA-approved small-molecules derived from Connectivity Map (cMAP). Here, we identified a compound and pathways that enhance the proliferation and anti-tumor function of NK cells using cMAP and integration of RNA-Seq and ChIP-Seq. We show that Vorinostat and Dexamethasone, obtained from cMAP, effectively induce NK cell proliferation. Methods, Results & Conclusion Dexamethasone reduces NK cell cytotoxicity, while Vorinostat increases it in vitro. RNA-Seq analyses reveal upregulated response to hypoxia and glucose metabolic process. In addition, RNA-Seq analyses indicating downregulated p21/p53 apoptotic pathways along with downregulation of pro-apoptotic genes, BAK, BAX, BIM, and FAS were accountable for highly proliferative NK cells via increased p53 acetylation. Integration of RNA-Seq and ChIP-Seq (H3K27ac) analyses also reveal reduction of apoptotic process. Upregulation of glucose metabolic process in Vorinostat treated NK cells resulted in increased anti-tumor activity with enhanced survival both in-vitro and in-vivo. Therefore, Vorinostat triggers NK cells to initiate coordinated regulation of apoptosis and cytotoxicity at the global gene transcriptional and epigenetic levels. Our results uncover a previously unidentified role of Vorinostat that can outperform tumor killing activity and survival of NK cells within a solid tumor for adoptive cellular therapy for successful clinical outcome.