Interleukin-37 is highly expressed in regulatory T cells of melanoma patients and enhanced by melanoma cell secretome

Mol Carcinog. 2019 Sep;58(9):1670-1679. doi: 10.1002/mc.23044. Epub 2019 May 16.


Immune suppression is one of the 10 hallmarks of cancer. Interleukin-37 (IL-37), a member of the IL-1 family, inhibits both innate and adaptive immunity, and has been shown to modulate immune responses in various disease conditions. Yet, IL-37 has rarely been investigated in cancer patients, and its biological role in cancer remains to be elucidated. In this study, we investigated the gene expression of IL-37 in age- and sex-matched blood samples of healthy individuals and melanoma patients, and demonstrated upregulation of IL-37 messenger RNA (mRNA) in the blood samples of melanoma patients. By further analyzing immune cell subsets responsible for the upregulated IL-37 expression, we discovered that IL-37 mRNA was highly expressed in T cells and granulocytes, with the highest expression in regulatory T (Treg ) cells in healthy individuals, and that IL-37 mRNA was upregulated in lymphocytes (T, B, and natural killer cells) in melanoma patient blood. Among all cell subsets, Treg cells from melanoma patients exhibited the highest IL-37 gene expression levels. We provided evidence that melanoma-conditioned media induces IL-37 mRNA and protein expression in multiple lymphocyte populations, particularly in Treg cells. We further confirmed that the IL-1-mediated secretome from human melanoma cells, specifically transforming growth factor-β, induces IL-37 mRNA expression in human Treg cells. Our results suggest a potential immunosuppressive role for IL-1 and IL-37 in melanoma tumorigenesis. Highly elevated IL-37 in specific lymphocyte populations could serve as a biomarker for tumor-induced immunosuppression.

Keywords: IL-37; Treg cells; blood; melanoma; secretome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biomarkers, Tumor / metabolism
  • Cells, Cultured
  • Female
  • Humans
  • Interleukin-1 / metabolism*
  • Male
  • Melanoma / metabolism*
  • RNA, Messenger / metabolism
  • T-Lymphocytes, Regulatory / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation / physiology


  • Biomarkers, Tumor
  • IL37 protein, human
  • Interleukin-1
  • RNA, Messenger
  • Transforming Growth Factor beta