A protective role of IL-37 in cancer: a new hope for cancer patients

Abstract

IL-37 is a cytokine belonging to the IL-1 family. Although discovered in silico in 2000, significant advances in the understanding of its biology were made only in recent years. It is a member of the family with potent anti-inflammatory and immunosuppressive properties. It is produced as a precursor without a classic signal peptide. The precursor is cleaved into mature form in the cytoplasm by caspase-1. A small fraction of the cleaved IL-37 binds SMAD-3, translocates to the nucleus, and suppresses transcription of several proinflammatory genes. Both precursor and cleaved forms of IL-37 are secreted. They bind IL-18Rα chain (also used by IL-18 as a receptor subunit) and recruit Toll/IL-1R (TIR)-8 for transducing intracellular signaling. TIR-8 is a member of the IL-1 receptor family (IL-1RF) and was previously known as an orphan receptor. IL-37 suppresses activation of NF-κB and MAPK and activates Mer-PTEN-DOK pathway. It negatively regulates signaling mediated by TLR agonists, proinflammatory cytokines, and IL-1RF ligands. It also affects cell metabolism by inhibiting mTOR, GSK-3α/β, and activating AMPK. Despite having the ability to dampen host's immune responses, the cytokine has been shown to exert antitumor effects, and it has been suggested that it may act as a prognostic marker in a variety of human cancers. Recent studies have suggested that IL-37 may represent a novel therapeutic tool in patients with cancer. In this review, we provide an overview of the cytokine biology, discuss recent advances made in unraveling its anti-cancer effects, and suggest guidelines for future research.

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

“…IL‐37 has shown anti‐inflammatory and immune suppression effects. IL‐37 contributes to the immunosuppressive property of human regulatory T cells, and its antitumor activity was identified by the recruitment of more natural killer cells in hepatocellular carcinoma 11, 13. In addition, we found that low IL‐37 expression and dMMR status are associated with high CD66b + TAN levels in CRC.…”

“…Nevertheless, entirely distinct with most IL‐1 family members, that are characterized with proinflammatory functions, IL‐37 has emerged as an important inhibitor of the innate immune response. With the accumulated evidence, IL‐37 has been recognized as a typical anti‐inflammatory cytokine related to autoimmune diseases, endotoxemia, inflammatory liver injury, obesity, and cancer 8, 9, 10, 11, 12. Gao et al9 found that the intratumoral injection of IL‐37 inhibited tumor growth and the antitumor activity of IL‐37 was abrogated in mice models.…”

IL‐37: An anti‐inflammatory cytokine with antitumor functions

“…It has been well established that inflammation is closely related to carcinogenesis . As an anti‐inflammatory cytokine, many studies have suggested the antitumor role of IL‐37 in various tumor types, which have been reviewed previously . Here, we will describe the most recent progress for the role of IL‐37 in fibrosarcoma, breast cancer, lung cancer, ovarian cancer, renal cell carcinoma (RCC), oral squamous cell carcinoma (OSCC), cervical cancer, colon cancer, multiple myeloma (MM), prostate cancer, and HCC.…”

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

“…Conversely, anti‐inflammatory IL‐37 might suppress tumorigenesis by inhibiting protumorigenic inflammation. Indeed, the protective role of IL‐37 in cancer has been reported when IL‐37 was transfected into cancer cells, or when recombinant IL‐37 was administered in animal models of cancers (summarized in review papers by Ding et al and Abulkhir et al). However, only limited studies have used cancer patient samples to investigate IL‐37 .…”