ERK5 modulates IL-6 secretion and contributes to tumor-induced immune suppression |
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| Authors: | Kristina Riegel Hajime Yurugi Janine Schlder Helmut Jonuleit Manuel Kaulich Friederike Kirschner Danielle Arnold-Schild Stefan Tenzer Hansjrg Schild Krishnaraj Rajalingam |
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| Institution: | 1.Cell Biology Unit, University Medical Center Mainz, JGU-Mainz, Mainz, Germany ;2.Department of Dermatology, University Medical Center Mainz, JGU-Mainz, Mainz, Germany ;3.Gene Editing Group, Institute of Biochemistry II, Goethe University, Frankfurt, Germany ;4.Institute of Immunology, University Medical Center Mainz, JGU-Mainz, Mainz, Germany |
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| Abstract: | Tumors exhibit a variety of strategies to dampen antitumor immune responses. With an aim to identify factors that are secreted from tumor cells, we performed an unbiased mass spectrometry-based secretome analysis in lung cancer cells. Interleukin-6 (IL-6) has been identified as a prominent factor secreted by tumor cells and cancer-associated fibroblasts isolated from cancer patients. Incubation of dendritic cell (DC) cultures with tumor cell supernatants inhibited the production of IL-12p70 in DCs but not the surface expression of other activation markers which is reversed by treatment with IL-6 antibody. Defects in IL-12p70 production in the DCs inhibited the differentiation of Th1 but not Th2 and Th17 cells from naïve CD4+ T cells. We also demonstrate that the classical mitogen-activated protein kinase, ERK5/MAPK7, is required for IL-6 production in tumor cells. Inhibition of ERK5 activity or depletion of ERK5 prevented IL-6 production in tumor cells, which could be exploited for enhancing antitumor immune responses.Subject terms: Cancer microenvironment, Extracellular signalling molecules |
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