ERK5 modulates IL-6 secretion and contributes to tumor-induced immune suppression

• Published in: Cell death & disease 2021-10, Vol.12 (11), p.969-969, Article 969
• Main Authors: Riegel, Kristina, Yurugi, Hajime, Schlöder, Janine, Jonuleit, Helmut, Kaulich, Manuel, Kirschner, Friederike, Arnold-Schild, Danielle, Tenzer, Stefan, Schild, Hansjörg, Rajalingam, Krishnaraj
• Format: Article
• Language: English
• Subjects: 13/31; 38/89; 631/67/327; 631/80/86/820; 82/58; 82/80; 96/106; 96/63; 96/95; Antibodies; Antitumor activity; Biochemistry; Biomedical and Life Sciences; Cancer; CD4 antigen; Cell Biology; Cell Culture; Cell Differentiation - immunology; Cell Line, Tumor; Cell Survival; Dendritic cells; Dendritic Cells - metabolism; Fibroblasts; Helper cells; Humans; Immunology; Immunosuppression Therapy; Interleukin 12; Interleukin 6; Interleukin-12 - metabolism; Interleukin-6 - metabolism; Kinases; Life Sciences; Lung cancer; Lymphocytes T; MAP kinase; Mass spectroscopy; Mitogen-Activated Protein Kinase 7 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 7 - metabolism; Models, Biological; Monocytes - metabolism; Neoplasms - immunology; Neoplasms - pathology; Protein kinase; RNA, Small Interfering - metabolism; Secretome; Th1 Cells - immunology; Tumor cells
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04257-8

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.