Global survey of the immunomodulatory potential of common drugs

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. Surprisingly, some 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, potentially contributing 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 MST1R/RON (macrophage-stimulating protein receptor) and subsequent upregulation of MHC (major histocompatibility complex) expression. The approach offers an attractive platform for the personalized identification and characterization of immunomodulatory therapeutics.

Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study

“…Here, we investigate the clinical impact of a newly developed technology platform that combines multiparametric immunofluorescence with high-throughput automated microscopy and single-cell image analysis, called pharmacoscopy. 30 Pharmacoscopy enables tumour-cell specific quantification of biological parameters of millions of adherent and non-adherent individual cells with high sample efficiency, minimal sample manipulation, extensive automation, and fast turn-around times. We thus aimed to evaluate the feasibility of integrating pharmacoscopy into the clinic, and to assess clinical response in patients who received a treatment according to pharmacoscopy results as an individual healing attempt.…”

PySpacell: A Python Package for Spatial Analysis of Cell Images

“…microscopy image in Fig.3b) were segmented following a few steps: namely a background illumination correction, an Otsu thresholding on the Hoechst channel, then a maxima detection, and a seeded watershed. The Moran's statistics is an autocorrelation measure that PySpacell can compute at several scales (cf x-axis of Fig.3c): from an immediate neighborhood, for example, k in [1,5] corresponds to the first five neighbors, or a further one, for example, k in [15,20] corresponds to the cells being ranked from 15th to 20th nearest neighbors. The correlogram of Figure 3c shows that at a short scale Moran's statistics values for the mean fluorescence ratio are positive, which means that similar fluorescence values spatially cluster together.…”

Precision Medicine Concepts in T-Cell Lymphoma

“…This could maintain leukemia and multiple myeloma cells for a longer cultivating time and enhance the screening capabilities of patient samples [45][46][47]. Snijder and colleagues investigated the clinical impact of a newly developed single-cell image analysis technology platform that operates using a combination of multi-parametric immunofluorescence and high-throughput automated microscopy [48]. In contrast to functional methods used previously, this next-generation functional drug screening (ngFDS) technique allows a fast tumor cell -specific quantification of biological parameters of millions of adherent and non-adherent individual cells with high sample efficiency, minimal sample manipulation, extensive automation, and fast turnaround times [49] (Figure 5).…”

“…Further, the platform can take advantage of the use of liquid biopsies where small target cells can be detected. These integrated drug response profiles, or "chemotypes," of individual people are the culmination of the interplay between a number of molecular parameters of the responding cells, including not only the genetic, proteomic, and metabolic state of the cells but also the direct and indirect molecular interactions with other cells [48], recapitulating relevant physiological complexity. Such chemotypes may offer functional insight into the underlying health status of an individual, with potentially wide-ranging implications also in preventative and participatory medicine.…”