H. Lee Moffitt Cancer Center and Research Institute Tampa United States
Multiple studies show that leukocytes infiltrating solid tumors have a hyporesponsive phenotype, yet the various molecular pathways remain unclear. We found one novel mechanism by TGFb, abundant in the tumor microenvironment, which induces miR-183 in human NK cells to downregulate the stimulatory signaling protein, DAP12 shutting down NK tumoricidal function. The goal of this project is to target miR-183 as a new therapeutic strategy to restore DAP12 in NK cells and recover immune function against cancer. Using immunodeficient NSG mice, the protocol is to optimize conditions to deliver anti-sense miR183 to NSG mice bearing human A549 lung tumors in combination with intravenous administration of human NK cells. The design of the anti-sense miR183 vector and its testing in vitro for efficacy is then followed by its use in vivo in tumor bearers to reconstitute NK function for regression of the established tumor.