High-content single-cell screening enables the discovery and classification of the immunomodulatory potential of drugs
Gregory I. Vladimer1*, Berend Snijder1,2*, Nikolaus Krall1, Kilian V.M. Huber1,3, Kumar Sanjiv4, Giulio Superti-Furga1,5
1CeMM, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;
2Department of Biology, Institute for Molecular Systems Biology, ETH Zurich, Zurich Switzerland; 3Structural Genomics Consortium, University of Oxford, Oxford, UK; 4Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; 5Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
*These authors contributed equally
Harnessing the immune system as a therapeutic tool is a hallmark of modern cancer treatment, with immunomodulatory drugs, biologics, and CAR-T cells at the forefront. Many of these interventions induce the interaction of effector and cancer cell (e.g. bi-specifics) thereby effectively reducing the malignant cell burden through cell-induced cytotoxicity. However, the discovery of such tools, especially small molecules, and the determination of the effective potential of pre-clinical entities, is difficult – due in part to the lack of robust technology and ex vivo model systems.
To this end, we have developed a single-cell technology powered by high-content and high-throughput fluorescent microscopy. Using specially designed image analysis pipelines and algorithms, we can robustly quantify immune system modulation. This is done by measuring the interaction propensity of cells to each other (cell-cell contact screening), and comparing how the propensity of specific populations is altered by external stimuli (e.g. drugs). Analyzing cell-cell contacts at the single-cell level enables robust determination of a population-wide immune response.
From a library of 1400 compounds, we find about 10% of FDA approved drugs have immunomodulatory capability. For instance, the ALK inhibitor Crizotinib, approved for non-small cell lung cancer, induces interaction of T-cells and target cells. This occurs via upregulation of MHC-II – inducing increases in cell-scanning – by blocking MST1R signaling within the target cell. This is in line with previously published reports that lung cancer models of MST1R KO mice have decreased tumor burden and increased T-cells within the lung tissue. This immunomodulatory phenotype of Crizotinib may contribute to its clinical efficacy.
With this system, we can robustly quantify the immunomodulatory potential of drugs by measuring changes in physical interactions of leukocytes over whole populations. Phenotypic screening can now be expanded to discover entities that can direct effector cells in peripheral blood to target cancer - a goal of immunotherapy. Further, it can map effects of external stimuli on immune function, providing a research resource.
Funding acknowledgement: EMBO, Swiss National Science Foundation, Austrian Science Fund (FWF), ERC
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