Modulation of pericytes by a fusion protein comprising of a PDGFRβ-antagonistic affibody and TNFα induces tumor vessel normalization and improves chemotherapy

Abstract

The delivery of anticancer drugs is hampered by tumor vessels with abnormal structure and function, which requires that vessel normalization be mediated by pharmaceutics. The current strategies for vessel normalization focus on direct modulation of endothelial cells (ECs), which frequently affect vessels in normal tissues. Modulating EC-supporting cells, such as pericytes (PCs), is a new direction. Here, we produced a fusion protein, Z-TNFα, by fusing the platelet-derived growth factor receptor β (PDGFRβ)- antagonistic affibody ZPDGFRβ to tumor necrosis factor α (TNFα). Owing to the affinity of fused ZPDGFRβ for PDGFRβ, Z-TNFα binds PDGFRβ+ PCs but not PDGFRβ− ECs. Low-dose (1 μg/mouse) Z-TNFα treatment remodeled the tumor vessels, thus reducing vessel permeability and increasing vessel perfusion. As a result, the Z-TNFα treatment improved the delivery of doxorubicin (DOX) and enhanced its antitumor effect, indicating that Z-TNFα induced normalization of tumor vessels. Mechanically, the tumor vessel normalization mediated by Z-TNFα might be attributed to the reduction of vascular endothelial growth factor (VEGF) secretion by PCs and the elevated expression of intercellular cell adhesion molecule-1 (ICAM-1) in PCs, which might suppress the proliferation and migration of ECs and simultaneously trigger interaction between perivascular macrophages and PCs. These results demonstrated that tumor-associated PCs could be considered novel target cells for vessel normalization, and Z-TNFα might be developed as a potential tool for antitumor combination therapy.