Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shannxi 710061, People's Republic of China.
Cell Chem Biol. 2019 Mar 21;26(3):331-339.e3. doi: 10.1016/j.chembiol.2018.11.011. Epub 2019 Jan 10.
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.
蛋白和细胞为基础的免疫治疗药物已经彻底改变了癌症治疗。然而，小分子免疫调节剂具有到达细胞内靶点的有利药理学特性，仍有待开发。为了探索广阔的化学空间，需要开发一种能够在高通量格式中重现复杂的癌症免疫微环境的强大方法。为了解决这一关键差距，我们开发了一种高通量免疫调节剂表型筛选平台 HTiP，它将免疫和癌细胞共培养系统与基于成像和生化的多重读出相结合。使用 HTiP 平台，我们已经证明了它在模拟致癌 KRAS 突变驱动的免疫抑制表型方面的能力。从一个生物活性化学文库中，鉴定出了多种结构不同的化合物，它们都针对同一类蛋白质，即凋亡抑制蛋白 (IAP)。IAP 在癌症免疫中具有作用。鉴定 IAP 拮抗剂作为有效的抗肿瘤免疫增强剂，为使用 HTiP 平台发现小分子免疫调节剂提供了强有力的验证证据。
