Using high-throughput phenotypic screening to identify therapeutic targets for the inhibition of myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with immunosuppressive function, which inhibit the antitumor activity of T-cells and natural killer (NK) cells. MDSC number is greatly increased in tumor-bearing mice and in cancer patients, and in the clinic, MDSC accumulation is associated with cancer progression, recurrence, and poor response to chemo-, radio- and immunotherapies. The increasing evidence for the clinical significance of MDSC has triggered a strong interest in the therapeutic modulation of their function. To date, however, limited progress has been made in this direction, as a major challenge in the field remains the identification of suitable therapeutic targets for the development of novel drugs. Here, we describe a systematic approach in which a small-molecule high-throughput phenotypic screen was used to identify MDSC targets and pathways of therapeutic relevance. This screen was based on a validated in vitro mouse mononuclear MDSC (M-MDSC) model, in which hematopoietic progenitors, immortalized using a NUP98/HOXB4 transgene, were differentiated into immunosuppressive MDSC. Using this model, we developed a 384-well-based phenotypic screening assay, in which the suppressive effect of mouse M-MDSC on CD8+ T-cell proliferation and cytokine secretion was monitored. We screened a small molecule library, comprising 5000+ biologically active compounds with known target(s), and identified 116 compounds that potently disrupted MDSC suppression of T-cell function. With the help of chemoinformatics methods, reported target activities associated with the compounds were annotated, and a set of targets and pathways of potential significance for MDSC-driven immunosuppression was identified. Altogether, this work provides insight into the signaling nodes that could be of relevance for MDSC function, and offers a path forward for the therapeutic targeting of MDSC. Citation Format: Elissaveta Petrova, Sandra Schaffner, Jan-Carsten Pieck, Christian Herhaus, Friedrich Rippmann, Oliver Poschke, Laura Helming. Using high-throughput phenotypic screening to identify therapeutic targets for the inhibition of myeloid-derived suppressor cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A099.