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

Douglas G. Osborne, Joanne Domenico, Yuchun Luo, Anna L. Reid, Carol Amato, Zili Zhai, Dexiang Gao, Melanie Ziman, Charles A. Dinarello, William A. Robinson, Mayumi Fujita

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Abstract

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.

Original languageEnglish
Pages (from-to)1670-1679
Number of pages10
JournalMolecular Carcinogenesis
Volume58
Issue number9
DOIs
Publication statusPublished - 1 Jan 2019

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Osborne, D. G., Domenico, J., Luo, Y., Reid, A. L., Amato, C., Zhai, Z., ... Fujita, M. (2019). Interleukin-37 is highly expressed in regulatory T cells of melanoma patients and enhanced by melanoma cell secretome. Molecular Carcinogenesis, 58(9), 1670-1679. https://doi.org/10.1002/mc.23044