Differential roles of tumoral and systemic IL-1α in the development of hepatocellular carcinoma

Abstract

Abstract Interleukin-1α (IL-1α) is a pro-inflammatory cytokine that has been shown to be up-regulated in many tumors. However, the role of IL-1α during tumor development is still not clear. IL-1α could be released by necrotic tumor cells passively to the tumor microenvironment or by other cells actively during inflammation. In the current study, we investigated the role of secreted IL-1α released in the tumor microenvironment or systemically in the tumor development using murine hepatocellular carcinoma (HCC) models. We constructed murine HCC hepa1-6 cells stably expressing secreted IL-1α and overexpression of secreted IL-1α had no significant effect on tumor cell proliferation and apoptosis in vitro. Tumor cells expressing secreted IL-1α were orthotopically implanted in the liver. Tumoral IL-1α significantly promoted HCC tumor development. Further studies showed that tumoral IL-1α inhibited T and NK cell activation, and attenuated the cytotoxic T lymphocyte (CTL) cytotoxic activity against tumor cells. Moreover, MDSCs were increased by tumoral IL-1α, and depletion of MDSCs could diminish the effect of the released IL-1α on tumor growth. On the contrary, systemic administration of IL-1α significantly inhibited the tumor development in the same murine HCC models. Systemic administration of IL-1α promoted T cell activation and decreased MDSCs in the tumor microenvironment. Further in vitro experiments showed that recombinant IL-1α could promote T cell activation and enhance CTL cytotoxicity. In conclusion, our studies demonstrated the differential functions of tumoral and systemic IL-1α in HCC development. Thus, our finding provides new insights of IL-1α functions in anti-tumor immunity with implications for tumor immunotherapy.