HTiP: High-Throughput Immunomodulator Phenotypic Screening Platform to Reveal IAP Antagonists as Anti-cancer Immune Enhancers

• Type of Material: Article
• Authors: Xiulei Mo, Emory University; Cong Tang, Emory University; Qiankun Niu, Emory University; Tingxuan Ma, Emory University; Yuhong Du, Emory University; Haian Fu, Emory University
• Language: English
• Date: 2019-03-21
• Publisher: Cell Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chembiol.2018.11.011
• Title of Journal or Parent Work: Cell Chemical Biology
• Volume: 26
• Issue: 3
• Start Page: 331
• End Page: +
• Grant/Funding Information: This research was supported in part by NIH NCI U01CA217875, NIH NCI 5U01CA199241 and a Georgia Cancer Coalition Award from Georgia Research Alliance, the Emory Chemical Biology Discovery Center, and Winship Cancer Institute (NIH 5P30CA138292).
• Keywords: Antibodies; Costimulation; T-cells; Activation; Inhibitors; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; SMAC mimetic; Science & Technology; Apoptosis
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Immunology; Biology, Cell; Chemistry, Biochemistry

Abstract

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. 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.