CXCL10 Secreted by Pericytes Mediates TNFα-Induced Vascular Leakage in Tumors and Enhances Extravasation of Nanoparticle-Based Chemotherapeutics.

Abstract Tumor necrosis factor-alpha (TNFα) induces vascular permeability and plays an important role in inflammation. In addition, TNFα-induced vascular leakage is involved in the increased extravasation of nanoparticle-formulated chemotherapeutic drugs, improving drug delivery and subsequent tumor response. Here, we uncovered a positive correlation between the presence of pericytes in the tumor-associated vasculature and TNFα-induced leakage and drug delivery, especially when drugs were encapsulated in nanoparticles. RNA-sequencing and pathway analysis identified high expression of CXCL10 in TNFα-stimulated pericytes. In addition, TNFα increased CXCL10 protein production by pericytes in vitro. In animal studies, tumor types with vessels with high pericyte coverage showed enhanced permeability and extravasation of drugs encapsulated in nanoparticles following treatment with TNFα, which could be blocked with a CXCL10 neutralizing antibody. In contrast, tumors harboring vessels with low pericyte numbers did not display increased drug extravasation in response to TNFα. Lack of pericyte coverage could be compensated by co-administration of CXCL10. These findings reveal a mechanism by which TNFα induces CXCL10 release from pericytes, resulting in increased endothelial permeability, vascular leakage, and drug delivery.