HTS for the discovery of activators of NK cell cytotoxicity

Abstract Natural killer (NK) cells are lymphocytes that are capable of killing malignant cells without antigen-specific receptor recognition. Due to this property, NK cells have been utilized for adoptive immune cell therapy for a variety of malignancies. Despite limited success for hematologic malignancies, the therapeutic potential of NK cell therapy for cancer has been limited by the insufficient cytotoxic activity of NK cells particularly for solid tumors. Due to the ability of NK cells to specifically target cancer cells and avoid killing of normal cells, we hypothesize that enhancing the cytotoxic activity of NK cells can lead to enhanced efficacy of NK cell therapies for cancer. As the molecular mediators regulating NK cell cytotoxic activity are still not fully characterized, we will conduct a small molecule high throughput compound library screen to identify novel mediators of NK cell cytotoxic activity. The purpose of this work is to identify small molecules that can be further developed for therapeutic purposes as well as to reveal important probes to elucidate mechanistic insights into NK cell activity that may enable future targeted approaches. In the first aim, we will identify compounds that enhance NK cell killing of ovarian cancer cells through a HTS of a diverse 300k small molecule collection. In the second aim, the primary hits will be tested in a series of secondary assays to identify the most promising hits. The most promising hits will then undergo biological characterization in vitro and in vivo. It is hoped that this work will lead to the identification of promising approaches to improve NK cell therapy for cancer patients.