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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.

Original publication

DOI

10.1038/nchembio.2360

Type

Journal article

Journal

Nature chemical biology

Publication Date

06/2017

Volume

13

Pages

681 - 690

Addresses

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

Keywords

Cell Line, Tumor, Humans, Colonic Neoplasms, Pyrazoles, Pyridines, Cardiac Myosins, Myosin Heavy Chains, Small Molecule Libraries, Immunomodulation