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

Cell Death Dis. 2021 Oct 20;12(11):969. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Cell Survival
  • Dendritic Cells / metabolism
  • Humans
  • Immunosuppression Therapy*
  • Interleukin-12 / metabolism
  • Interleukin-6 / metabolism*
  • Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Models, Biological
  • Monocytes / metabolism
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • RNA, Small Interfering / metabolism
  • Th1 Cells / immunology


  • Interleukin-6
  • RNA, Small Interfering
  • Interleukin-12
  • MAPK7 protein, human
  • Mitogen-Activated Protein Kinase 7