FUNCTIONS OF IL-37A IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC)

Abstract

Human Interleukin 37 (IL-37) is a cytokine belonging to IL-1 family. IL-37b isoform was reported to exert protective, anti-tumor effects in hepatocellular carcinoma (HCC). The role of IL-37a isoform in HCC development is currently unknown. In this study we explored the function of IL-37a in HCC development. Interestingly, in contrast to IL-37b, IL-37a promoted HCC tumor development in vivo, in an NK cell dependent manner. Further studies revealed that IL-37a decreased the distribution of liver resident NK cells (LrNKs) and led to their dysfunction in HCC tumor microenvironment (TME). Mechanistically, we showed that IL-37a upregulated genes associated with lipid metabolism and transport while upregulating scavenger receptor (SR) expression on LrNK cells, which promoted their intracellular lipid accumulation. This in turn decreased their granzyme B and interferon-γ expression. This reduction in interferon-γ expression by LrNK cells subsequently affected their own development. In conclusion, we proved that IL-37a dampened anti-tumor activity of LrNK cells to promote HCC development.