IL-37 mediates the anti-tumor activity in hepatocellular carcinoma via T cell activation and angiogenesis suppression

Abstract

Abstract IL-37 has been shown to play an immunosuppressive role against inflammatory and autoimmune diseases. However, the role of IL-37 in tumor development is still controversial. Recent studies demonstrated that IL-37 could recruit NK cells, stimulate CD4+ T cell activation, as well as inhibit tumor angiogenesis to suppress tumor progression in different tumor models. Other studies suggested that IL-37 could affect DC function to suppress adaptive immune response. In the current study, we found that IL-37 could directly inhibit hepatocellular carcinoma (HCC) cell expansion and promote its apoptosis. The in vivo results showed that IL-37 could inhibit HCC development through enhancing the T cell cytokine production and killing capacity in murine orthotopic HCC model and DEN-induced HCC model. This anti-tumor effect was fully abrogated in NOD-SCID mice. Furthermore, we found that IL-37 could also inhibit tumor angiogenesis in peritumoral areas. The in vitro study showed that recombinant IL-37 protein could directly promote the migration, tube formation and IL-1R8, VEGF, MMP2 expression in HUVEC cells. However, the supernatant from IL-37 expressing HCC cells showed an inhibition on the HUVEC cell migration and tube formation, suggesting its secondary role on angiogenesis through tumor cells could be dominant in the tumor microenvironment. Overall, these results showed that IL-37 could suppress HCC development through T cell activation and angiogenesis suppression.