HTiP: High-Throughput Immunomodulator Phenotypic Screening Platform to Reveal IAP Antagonists as Anti-cancer Immune Enhancers. Issue 3 (21st March 2019) - Mo, Xiulei
Summary: Protein- and cell-based immunotherapeutic agents have revolutionized cancer treatment. However, small-molecule immunomodulators with favorable pharmacological properties for reaching intracellular targets remain to be developed. To explore the vast chemical space, a robust method that recapitulates the complex cancer-immune microenvironment in a high-throughput format is essential. To address this critical gap, we developed a high-throughput immunomodulator phenotypic screening platform, HTiP, which integrates the immune and cancer cell co-culture system with imaging- and biochemical-based multiplexed readouts. Using the HTiP platform, we have demonstrated its capability in modeling an oncogenic KRAS mutation-driven immunosuppressive phenotype. From a bioactive chemical library, multiple structurally distinct compounds were identified, all of which target the same class of proteins, inhibitor of apoptosis protein (IAP). IAP has demonstrated roles in cancer immunity. Identification of IAP antagonists as potent anti-tumor immune enhancers provides strong validating evidence for the use of the HTiP platform to discover small-molecule immunomodulators. Graphical Abstract: Highlights: HTiP is a miniaturized co-culture system with cancer and immune cells HTiP integrates imaging- with biochemical-based readouts for built-in counterscreening HTiP models oncogenic KRAS mutation-induced immunosuppression HTiP screening identifies IAP inhibitors as anti-tumor immunity enhancers Abstract : Exploring the vast chemical space for immunotherapeutic agent discovery requires robust technologies that recapitulate the tumor-immune microenvironment. Mo et al. developed an HTiP platform that models the KRAS mutation-driven immunosuppressive phenotype. The identification of IAP inhibitors with known anti-tumor immunity activity supports the utility of HTiP to uncover small-molecule anti-cancer immunomodulators.