Abstract

Immunotherapeutic small molecules have emerged as a promising complement to current immunotherapies. High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated discovery of new cancer drugs and has given rise to a number of FDA-approved chemotherapeutics that are currently used in the clinic; however, most phenotypic HTS platforms used in the field of oncology are still based solely on cancer cells and do not allow for identification of immunomodulatory small molecules. To address this, we developed a phenotypic screening platform integrating both cancer- and immune cells grown in a miniaturized 384-well plate format. We screened 1,280 small molecule drugs and identified mevastatin, a member of the statin drug family, as an enhancer of anti-tumor immunity. Upon evaluation of additional statins, the lipophilic statins mevastatin, simvastatin, pitavastatin, lovastatin, and fluvastatin were all shown to potentiate anti-CD3/IL2 activated peripheral blood mononuclear cells (PBMCs) and increase immune cell-dependent elimination of colorectal cancer cells. Statins are widely prescribed to manage high cholesterol and are generally considered anti-inflammatory; the literature is however conflicted as several members of the statin drug family have been shown to also induce pro-inflammatory effects. Additionally, increasing preclinical and clinical observations supports an anti-cancer effect. We speculate that the clinical benefits recently described for cancer patients receiving statin treatment are dependent on the combined effect exerted on both cancer- and immune cells. In conclusion, we developed a phenotypic screening platform with a simple image-based readout that identified statins as enhancers of immune cell-dependent cancer elimination.