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. 2018 Mar;103(3):545-558.
doi: 10.1002/JLB.5MA0717-282R. Epub 2018 Jan 4.

Effects of IL-10 and Th 2 cytokines on human Mφ phenotype and response to CSF1R inhibitor

Leon P Pradel  1   2 , Andreas Franke  3 , Carola H Ries  1
Affiliations

Effects of IL-10 and Th 2 cytokines on human Mφ phenotype and response to CSF1R inhibitor

Leon P Pradel et al. J Leukoc Biol. 2018 Mar.

Abstract

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.

Keywords: IL-4 and -13; RG7155/emactuzumab; cancer immunotherapy; gene expression profiling; tumor-associated Mφ.

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