HIF-1α/IL-8 axis in hypoxic macrophages promotes esophageal cancer progression by enhancing PD-L1 expression.

Abstract

Esophageal cancer (EC) is a malignancy with poor prognosis and high mortality. Hypoxic microenvironment has also been proved to be an important feature of tumors. Herein, we mainly studied the influence of hypoxia-treated tumor-associated macrophages (TAMs) on EC malignant phenotype and related molecular mechanism. In this paper, we found that hypoxic macrophages contributed to EC cell proliferation, cell cycle progression, and metastasis. Besides, the hypoxia treatment expedited the transformation of macrophages into M2 polarization. The level of interleukin (IL)-8 was boosted in macrophages after hypoxia treatment. Moreover, hypoxia treatment heightened IL-8 secretion by macrophages via positively regulating hypoxia-inducible factor-1α (HIF-1α) expression. The IL-8 secreted by hypoxic macrophages facilitated EC cell proliferation, cell cycle progression, and metastasis by elevating ligand of programmed death 1 (PD-L1) expression. In the end, IL-8 also expedited EC tumorigenesis in vivo. In conclusion, HIF-1α/IL-8 axis in hypoxic macrophages could expedite EC advancement by upregulating PD-L1 level, which might deliver a novel thought for EC cure.