IL-37 induces anti-tumor immunity by indirectly promoting dendritic cell recruitment and activation in hepatocellular carcinoma

INTRODUCTION: IL-37 is a cytokine of IL-1 family that plays an important role in innate immunity and inflammation, and has been studied as a tumor suppressor in many cancers. However, it remains unclear whether IL-37 plays a regulatory role in tumor-infiltrating dendritic cells (DCs) in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We evaluated the relationship between IL-37 expression and tumor infiltration by DCs in 155 HCC samples through immunohistochemical analysis and Kaplan–Meier survival analysis. The effects of IL-37 on the anti-tumor activity of DCs were investigated by ELISA, flow cytometry, real-time quantitative PCR, cytotoxicity assays and tumorigenicity assays. RESULTS: The expression level of IL-37 in HCC samples was positively correlated with the degree of CD1a(+) DCs infiltration. The survival rates of patients with both a high expression of IL-37 and a high infiltration by CD1a(+) DCs were significantly higher than those of patients with a low expression of IL-37 and a low infiltration by CD1a(+) DCs. In vitro chemotaxis analysis indicated that HCC cells overexpressing IL-37 recruited more DCs by secreting higher levels of specific chemokines (eg, CCL3 and CCL20). In addition, IL-37 indirectly up-regulated the expression of major histocompatibility class II molecules, CD86 and CD40 on DCs by acting on tumor cells; IL-37 also indirectly enhanced the anti-tumor effect of T lymphocytes by stimulating DCs to secrete cytokines such as IL-2, IL-12, IL-12p70, interferon-α (IFN-α) and IFN-γ. Finally, overexpression IL-37 in HCC cells significantly delayed tumor growth and increased recruitment of CD11c(+) DCs to tumor tissues was also revealed in vivo mouse model. CONCLUSION: DCs play an important role in IL-37 mediated anti-tumor immune responses in HCC, which may contribute to the development of novel cancer immunotherapeutic strategies.