The effects of hypoxia-inducible factors on tumor macrophages in the tumor microenvironment and tumor immunity

Abstract

The tumor tissue environment is considered hypoxic condition. The hypoxic condition inhibits hypoxia inducible factor (HIF) degradation and HIFs are constitutively active through prolylhydrosylase deactivation. Furthermore, in tumor cells, the activation of HIF-1a is considered as a tumor exacerbation factor that promotes proliferation, metastasis, and resistance to therapy in tumor cells. On the other hand, in immune cells, HIF-1α is involved in enhancing the inflammatory and immune response, activating T cells, and then acting as a tumor suppressor. These controversial things are not clear in vivo models. Therefore, it is needed to reveal whether upregulating HIFs level is beneficial for cancer therapy or not.

we have used Lewis lung carcinoma (LLC) syngeneic tumor mouse models and used macrophage-specific VHL knockout mice. Macrophage were collected from transplanted mice tumor and performed RNA-seq analysis. We explored genes that were highly expressed in tumor suppress macrophages and found candidate genes regulated by HIF. These candidate genes were evaluated and confirmed to be secreted from macrophages and inhibit tumor growth in vivo. These results suggest that upregulation of HIF-1 in macrophage could contribute to inhibit tumor growth.