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Global survey of the immunomodulatory potential of common drugs

Nature Chemical Biology volume 13, pages 681–690 (2017)Cite this article

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Abstract

Small-molecule drugs may complement antibody-based therapies in an immune-oncology setting, yet systematic methods for the identification and characterization of the immunomodulatory properties of these entities are lacking. We surveyed the immumomodulatory potential of 1,402 small chemical molecules, as defined by their ability to alter the cell-cell interactions among peripheral mononuclear leukocytes ex vivo, using automated microscopy and population-wide single-cell image analysis. Unexpectedly, ∼10% of the agents tested affected these cell-cell interactions differentially. The results accurately recapitulated known immunomodulatory drug classes and revealed several clinically approved drugs that unexpectedly harbor the ability to modulate the immune system, which could potentially contribute to their physiological mechanism of action. For instance, the kinase inhibitor crizotinib promoted T cell interactions with monocytes, as well as with cancer cells, through inhibition of the receptor tyrosine kinase MSTR1 and subsequent upregulation of the expression of major histocompatibility complex molecules. The approach offers an attractive platform for the personalized identification and characterization of immunomodulatory therapeutics.

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Figure 1: Quantifying PBMC cell-cell interactions that are perturbed by biologicals.
Figure 2: Screening for chemical modifiers of PBMC cell-cell contacts.
Figure 3: Crizotinib increases T cell interactions with monocytes through upregulation of MHC-II.
Figure 4: Crizotinib drives MHC-I expression in SW480 colon cancer cells.
Figure 5: Immunomodulatory effect of crizotinib is mediated by MST1R inhibition.
Figure 6: In vivo assessment of the immunomodulatory potential of crizotinib.

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Acknowledgements

We are grateful to the donors and patients for their part in this study. Our screening compound libraries are from the US National Institutes of Health clinical collection or as gifts from F. Bracher, T. Nielsen, S. Nijman, J. Bradner, the Broad Institute and Haplogen GmbH. JQ1 was provided by S. Knapp (University of Oxford), and H3122 cells and SW480 cells were kind gifts from E. Haura (Moffitt Cancer Center) and W. Berger (Medical University of Vienna), respectively. We thank M. Rebsamen, A. Fauster, G. Jurisic, A. César-Razquin, C.C. West, E. Girardi and G. Winter for assistance and critical reading of the manuscript and members of G.S.-F.'s laboratory for scientific discussions. CeMM is supported by the Austrian Academy of Sciences. We acknowledge funding from an ERC i-FIVE Advanced Investigator Grant (G.S.-F.), Austrian Science Fund grant F4711-B20 (G.S.-F.), the Austrian Federal Ministry of Science, Research and Economy (S.K.), the National Foundation for Research, Technology and Development (S.K.), the Swedish Cancer Society (T.H.), the Knut and Alice Wallenberg Foundation (T.H.), the Torsten and Ragnar Söderberg Foundation (T.H.), Swiss National Science Foundation Fellowships (P300P3_147897 (B.S.), PP00P3_163961 (B.S.) and P2EZP3_159114 (N.K.)), an EMBO long-term Fellowship (1543-2012; G.I.V.) and a Marie-Sklodowska Curie Action Fellowship (SLIM; N.K.).

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Author notes

  1. Berend Snijder

    Present address: Present address: Department of Biology, Institute of Molecular Systems Biology, Zurich, Switzerland.,

  2. Gregory I Vladimer and Berend Snijder: These authors contributed equally to this work.

Authors and Affiliations

  1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Gregory I Vladimer, Berend Snijder, Nikolaus Krall, Johannes W Bigenzahn, Kilian V M Huber, Charles-Hugues Lardeau, Anna Ringler, Monika Sabler, Oscar Lopez de la Fuente, Stefan Kubicek & Giulio Superti-Furga

  2. Structural Genomics Consortium, University of Oxford, Oxford, UK and Target Discovery Institute, University of Oxford, Oxford, UK

    Kilian V M Huber

  3. Christian Doppler Laboratory for Chemical Epigenetics and Anti-infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Charles-Hugues Lardeau, Anna Ringler & Stefan Kubicek

  4. Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden

    Kumar Sanjiv, Ulrika Warpman Berglund & Thomas Helleday

  5. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria

    Paul Knöbl & Ulrich Jäger

  6. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Giulio Superti-Furga

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Contributions

G.I.V., B.S., N.K., J.W.B., K.V.M.H., C.-H.L., K.S., A.R., U.W.B. and M.S. performed the experiments; P.K. and U.J. organized the clinical samples; S.K. and O.L.d.l.F. provided reagents and intellectual contributions; P.K., U.J., T.H. and G.S.-F. were responsible for human and animal ethical guidelines; G.S.-F. oversaw the project; and B.S., G.I.V. and G.S.-F. analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Giulio Superti-Furga.

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Competing interests

The spatial screening and interaction score for use in immunomodulatory drug discovery is patent-pending (WO2016046346) with G.I.V., B.S. and G.S.-F. listed as inventors. The patent is licensed to Allcyte GmbH (Vienna, Austria), which G.I.V., B.S., N.K. and G.S.-F. have co-founded.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1 and 2, and Supplementary Figures 1–6. (PDF 4603 kb)

Supplementary Dataset 1

Overview of 1,402 compounds used for screens. (XLSX 185 kb)

Supplementary Dataset 2

Resource: immune modulation potential of 1,402 compounds on key lymphocyte population interaction changes. (XLSX 243 kb)

Supplementary Dataset 3

RNA sequencing data from SW480 crizotinib treated cells. (XLSX 3984 kb)

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Vladimer, G., Snijder, B., Krall, N. et al. Global survey of the immunomodulatory potential of common drugs. Nat Chem Biol 13, 681–690 (2017). https://doi.org/10.1038/nchembio.2360

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