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Effects of IL‐10 and T h 2 cytokines on human Mφ phenotype and response to CSF1R inhibitor
Author(s) -
Pradel Leon P.,
Franke Andreas,
Ries Carola H.
Publication year - 2018
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.5ma0717-282r
Subject(s) - biology , phenotype , wnt signaling pathway , cytokine , interleukin 4 , receptor , signal transduction , immunology , microbiology and biotechnology , cancer research , gene , genetics
Tumor‐associated Mφs display a plastic phenotype that is regulated by the local tumor milieu. Gene expression analysis and functional characterization of Mφs exposed in vitro to individual cytokines aids to delineate the cross‐talk between defined cytokines shaping the complex Mφ phenotype. Human monocyte‐derived Mφs can be differentiated in vitro with the T helper cell type 2 response cytokines IL‐4 and IL‐13 or the immunosuppressive IL‐10. Notably, only the latter subset undergoes apoptosis when treated with the CSF 1 receptor (CSF1R) blocking antibody emactuzumab. However, under physiologic conditions, the Mφ phenotype is regulated by cytokine combination. Hence, in this study, we characterized the plasticity of IL‐4 or IL‐13‐differentiated Mφs upon exposure to the immunosuppressive IL‐10. Although IL‐4‐differentiated Mφs sustained their molecular phenotype in the presence of IL‐10, IL‐13‐differentiated Mφs were skewed towards the IL‐10 phenotype. Gene expression profiling revealed unique IL‐4+IL‐10 and IL‐13+IL‐10 Mφ signatures associated with up‐regulation of canonical NF‐κB or Wnt/β‐catenin signaling pathways, respectively. Although IL‐10 was able to alter the surface marker and gene expression profile of IL‐13‐differentiated Mφs, addition of IL‐10 did not restore emactuzumab susceptibility. Combining NF‐κB and Wnt/β‐catenin signaling inhibitors with emactuzumab had no effect on viability. On average 3–5% of cancer patients overexpressed IL‐4, IL‐13, or IL‐10 mRNA in silico. Although a small patient subset overexpressed IL‐10+IL‐13, IL‐4+IL‐10 lacked co‐expression. In vitro characterization of CSF1R inhibitor‐refractory Mφ phenotypes can support novel pharmacological approaches to specifically target these cells.