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

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.

Current Understanding of IL-37 in Human Health and Disease

“…The blood of melanoma patients contains lymphocytes (T, B, and natural killer cells) with increased IL-37 mRNA expression, with the highest expression in Treg cells (89). Similarly, Treg cells cultured in melanoma-conditioned media also express IL-37 mRNA and protein (89).…”

“…The blood of melanoma patients contains lymphocytes (T, B, and natural killer cells) with increased IL-37 mRNA expression, with the highest expression in Treg cells (89). Similarly, Treg cells cultured in melanoma-conditioned media also express IL-37 mRNA and protein (89). In addition, the IL-1mediated secretome from human melanoma cells, particularly TGF-b, induces IL-37 mRNA expression in human Treg cells (89).…”

IL-37 Represses the Autoimmunity in Myasthenia Gravis via Directly Targeting Follicular Th and B Cells

“…We found CD4 + T cell is the main source of IL-37 production. Although IL-37 could be released by Treg cells, one of the key subsets of CD4 T cell (56,57), unexpectedly, most producing T cells are Foxp3 and CD25 negative in MG patients. One of the possibility is that the IL-37 expression in Treg is also regulated by unique signals.…”

“…IL-37 was reported highly expressed in Treg cells of melanoma patients. In addition, melanoma condition media are capable of inducing IL-37 expression in Treg cells in both mRNA and protein levels significantly (57). Meanwhile, dysregulated Treg was reportedly associated with impaired IL-37 function/expression (56).…”

“…Foxp3 + or CD25 + CD4 T cells are traditional Treg cells and have been shown as the key primary source of IL-37 (56,57). IL-37 was suggested as one of the protein released by Treg cells to exert its immunosuppressive function (56,57). Unexpectedly, around 97.1 6 0.91% IL-37-producing T cells are Foxp3 negative, with only 2.4 6 0.43% IL-37 + CD4 + T cells expressed Foxp3 (Fig.…”