IL-37 suppresses hepatocellular carcinoma development through T cell activation and angiogenesis suppression

Abstract

Abstract IL-37, a relatively newly identified IL-1 family cytokine, has been shown to play an important immune regulatory role in inflammatory diseases, autoimmune diseases and carcinogenesis. IL-37 has been demonstrated to recruiting NK cells, stimulating CD4+ T cells, as well as inhibiting tumor angiogenesis to suppress tumor growth in various tumor models. In this current study, we found that IL-37 could suppress hepatocellular carcinoma (HCC) development in murine orthotopic HCC model and DEN-induced HCC model. Further study revealed that IL-37 could enhance the T cell killing capacity. This anti-tumor effect was fully abrogated in NOD-SCID mice. Furthermore, IL-37 could inhibit tumor angiogenesis in murine HCC model. In vitro study revealed that IL-37 treatment directly promoted HUVECs migration and tubule formation capacity, indicating IL-37 is a pro-angiogenic factor. However, the supernatant from IL-37 over-expression HCC cell line promoted HUVECs apoptosis and impaired the migration and tubule formation capacity of HUVECs. Microarray data suggested IL-37 affected the pro- and anti-angiogenic factors expression pattern from tumor cells. The pro-angiogenic factors ANGPT1, CYP1B1, FN1, MMP2, MCAM, PIK3CG were downregulated by IL-37, while the anti-angiogenic factor ANGPT1 was upregulated. These results indicated IL-37 could affect angiogenesis in both direct and indirect ways. Overall, our results demonstrated that IL-37 could suppress HCC development through T cell activation and angiogenesis suppression.