Transarterial Embolization Using an Inorganic Phosphate Binder Modulates Immunity- and Angiogenesis-Related Factors in a Rat Model of Liver Cancer

Abstract

Purpose

To determine how low inorganic phosphate stress (LIPS) induced by sevelamer particle transarterial embolization (S-TAE) affects immune regulation and angiogenesis in hepatocellular carcinoma.

Material and Methods

Transcatheter arterial embolization (TAE) using conventional ethiodized oil plus polyvinyl alcohol microspheres and S-TAE, which depletes intratumoral inorganic phosphate, were conducted on a McA-RH7777 orthotopic liver tumor model in rats, followed by the assessment of alterations in immunity-related and angiogenesis-related factors. The cells were cultured under hypoxic conditions and stimulated with LIPS to analyze the modulation of programmed cell death 1 ligand (PD-L1), vascular endothelial growth factor (VEGF)-α, and transforming growth factor-β1 expression using western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence assays. Cell migratory capacity and angiogenesis were also evaluated.

Results

TAE increased the expression of neoplastic PD-L1 and VEGF-α, and S-TAE downregulated the expression of PD-L1, VEGF-α, and transforming growth factor TGF-β1 and augmented the infiltration of CD8⁺ T cells, and thereby inhibited angiogenesis and activated anticancer immunity. In vitro, the study demonstrated that LIPS inhibited hypoxia-induced upregulation of PD-L1 expression and the hypoxia-inducible factor-1α/VEGF-α axis. Moreover, LIPS inhibited the tube formation ability of human umbilical vein endothelial cells and the migration ability and epithelial–mesenchymal transition process of cancer cells under hypoxic conditions.

Conclusions

S-TAE inhibited the expression of PD-L1 and VEGF-α, thereby activating antitumor immunity and suppressing tumor angiogenesis. The biology of tumors under LIPS suggests the potential therapeutic value of phosphate depletion using sevelamer for S-TAE.