Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Global survey of the immunomodulatory potential of common drugs

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

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Snijder, B. et al. Population context determines cell-to-cell variability in endocytosis and virus infection. Nature 461, 520–523 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Germain, R.N., Robey, E.A. & Cahalan, M.D. A decade of imaging cellular motility and interaction dynamics in the immune system. Science 336, 1676–1681 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mahoney, K.M., Rennert, P.D. & Freeman, G.J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14, 561–584 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Hoos, A. Development of immuno-oncology drugs—from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15, 235–247 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Sharma, P. & Allison, J.P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Roche, P.A. & Furuta, K. The ins and outs of MHC class II–mediated antigen processing and presentation. Nat. Rev. Immunol. 15, 203–216 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hou, W. et al. Viral infection triggers rapid differentiation of human blood monocytes into dendritic cells. Blood 119, 3128–3131 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Germain, R.N. & Stefanová, I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Wu, L.C., Tuot, D.S., Lyons, D.S., Garcia, K.C. & Davis, M.M. Two-step binding mechanism for T cell receptor recognition of peptide–MHC. Nature 418, 552–556 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Lolekha, S., Dray, S. & Gotoff, S.P. Macrophage aggregation in vitro: a correlate of delayed hypersensitivity. J. Immunol. 104, 296–304 (1970).

    CAS  PubMed  Google Scholar 

  12. Maloney, D.G., Smith, B. & Rose, A. Rituximab: mechanism of action and resistance. Semin. Oncol. 29, 2–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Löffler, A. et al. Efficient elimination of chronic lymphocytic leukemia B cells by autologous T cells with a bispecific anti-CD19–anti-CD3 single-chain antibody construct. Leukemia 17, 900–909 (2003).

    Article  PubMed  CAS  Google Scholar 

  14. Topp, M.S. et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B precursor acute lymphoblastic leukemia: a multicenter, single-arm, phase 2 study. Lancet Oncol. 16, 57–66 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Honke, N. et al. Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus. Nat. Immunol. 13, 51–57 (2011).

    Article  PubMed  CAS  Google Scholar 

  16. Hu, X., Li, W.P., Meng, C. & Ivashkiv, L.B. Inhibition of IFN-γ signaling by glucocorticoids. J. Immunol. 170, 4833–4839 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Glass, C.K. & Saijo, K. Nuclear receptor trans-repression pathways that regulate inflammation in macrophages and T cells. Nat. Rev. Immunol. 10, 365–376 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Dennis, E.A. & Norris, P.C. Eicosanoid storm in infection and inflammation. Nat. Rev. Immunol. 15, 511–523 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Harizi, H., Corcuff, J.B. & Gualde, N. Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology. Trends Mol. Med. 14, 461–469 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Ben-Zvi, I., Kivity, S., Langevitz, P. & Shoenfeld, Y. Hydroxychloroquine: from malaria to autoimmunity. Clin. Rev. Allergy Immunol. 42, 145–153 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Anderson, H.A., Hiltbold, E.M. & Roche, P.A. Concentration of MHC class II molecules in lipid rafts facilitates antigen presentation. Nat. Immunol. 1, 156–162 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Komaniwa, S. et al. Lipid-mediated presentation of MHC class II molecules guides thymocytes to the CD4 lineage. Eur. J. Immunol. 39, 96–112 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Weitz-Schmidt, G. et al. Statins selectively inhibit leukocyte function antigen 1 by binding to a novel regulatory integrin site. Nat. Med. 7, 687–692 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Schindler, R., Dinarello, C.A. & Koch, K.M. Angiotensin-converting-enzyme inhibitors suppress synthesis of tumor necrosis factor and interleukin 1 by human peripheral blood mononuclear cells. Cytokine 7, 526–533 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Flaishon, L. et al. Expression of the chemokine receptor CCR2 on immature B cells negatively regulates their cytoskeletal rearrangement and migration. Blood 104, 933–941 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Rice-Evans, C.A., Miller, N.J., Bolwell, P.G., Bramley, P.M. & Pridham, J.B. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic. Res. 22, 375–383 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Khajanchi, B.K., Kirtley, M.L., Brackman, S.M. & Chopra, A.K. Immunomodulatory and protective roles of quorum-sensing signaling molecules N-acyl homoserine lactones during infection of mice with Aeromonas hydrophila. Infect. Immun. 79, 2646–2657 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ritchie, A.J. et al. The Pseudomonas aeruginosa quorum-sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone inhibits T cell differentiation and cytokine production by a mechanism involving an early step in T cell activation. Infect. Immun. 73, 1648–1655 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Elenkov, I.J., Wilder, R.L., Chrousos, G.P. & Vizi, E.S. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52, 595–638 (2000).

    CAS  PubMed  Google Scholar 

  30. Alam, S., Laughton, D.L., Walding, A. & Wolstenholme, A.J. Human peripheral blood mononuclear cells express GABAA receptor subunits. Mol. Immunol. 43, 1432–1442 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Bhat, R. et al. Inhibitory role for GABA in autoimmune inflammation. Proc. Natl. Acad. Sci. USA 107, 2580–2585 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tian, J., Yong, J., Dang, H. & Kaufman, D.L. Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis. Autoimmunity 44, 465–470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sanders, V.M. The β2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav. Immun. 26, 195–200 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Loza, M.J., Foster, S., Peters, S.P. & Penn, R.B. β-agonists modulate T cell functions via direct actions on type 1 and type 2 cells. Blood 107, 2052–2060 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Heine, A., Held, S.A., Bringmann, A., Holderried, T.A. & Brossart, P. Immunomodulatory effects of anti-angiogenic drugs. Leukemia 25, 899–905 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Santoni, M. et al. Role of natural and adaptive immunity in renal cell carcinoma response to VEGFR-TKIs and mTOR inhibitor. Int. J. Cancer 134, 2772–2777 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Cui, J.J. et al. Structure-based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J. Med. Chem. 54, 6342–6363 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Kobayashi, K.S. & van den Elsen, P.J. NLRC5: a key regulator of MHC class I–dependent immune responses. Nat. Rev. Immunol. 12, 813–820 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Sharma, P. & Allison, J.P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Moreno, C.S., Beresford, G.W., Louis-Plence, P., Morris, A.C. & Boss, J.M. CREB regulates MHC class II expression in a CIITA-dependent manner. Immunity 10, 143–151 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Huber, K.V.M. et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature 508, 222–227 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Davis, M.I. et al. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol. 29, 1046–1051 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Christensen, J.G. et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol. Cancer Ther. 6, 3314–3322 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Wilson, C.B. et al. The RON receptor tyrosine kinase regulates IFN-γ production and responses in innate immunity. J. Immunol. 181, 2303–2310 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Eyob, H. et al. Inhibition of Ron kinase blocks conversion of micrometastases to overt metastases by boosting antitumor immunity. Cancer Discov. 3, 751–760 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mallakin, A. et al. Gene expression profiles of Mst1r-deficient mice during nickel-induced acute lung injury. Am. J. Respir. Cell Mol. Biol. 34, 15–27 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Schroeder, G.M. et al. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J. Med. Chem. 52, 1251–1254 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Lovly, C.M. et al. Rationale for co-targeting IGF-1R and ALK in ALK-fusion-positive lung cancer. Nat. Med. 20, 1027–1034 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Knight, Z.A., Lin, H. & Shokat, K.M. Targeting the cancer kinome through polypharmacology. Nat. Rev. Cancer 10, 130–137 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang, J., Yang, P.L. & Gray, N.S. Targeting cancer with small-molecule kinase inhibitors. Nat. Rev. Cancer 9, 28–39 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Fellmann, C. et al. An optimized microRNA backbone for effective single-copy RNAi. Cell Rep. 5, 1704–1713 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Trapnell, C. et al. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat. Biotechnol. 31, 46–53 (2012).

    Article  PubMed  CAS  Google Scholar 

  54. Trapnell, C. et al. Transcript assembly and quantification by RNA-seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511–515 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Winter, G.E. et al. Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. Nat. Chem. Biol. 8, 905–912 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rämö, P., Sacher, R., Snijder, B., Begemann, B. & Pelkmans, L. CellClassifier: supervised learning of cellular phenotypes. Bioinformatics 25, 3028–3030 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

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.).

Author information

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

Authors
  1. Gregory I Vladimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Berend Snijder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nikolaus Krall
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johannes W Bigenzahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kilian V M Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charles-Hugues Lardeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kumar Sanjiv
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anna Ringler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ulrika Warpman Berglund
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Monika Sabler
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Oscar Lopez de la Fuente
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Paul Knöbl
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stefan Kubicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thomas Helleday
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ulrich Jäger
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Giulio Superti-Furga
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

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)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.2360

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer