IFNγ blockade in capillary leak site improves tumour chemotherapy by inhibiting lactate-induced endocytosis of vascular endothelial-cadherins

IFN gamma has long been recognised as a key mediator of tumour immunity and angiostasis. However, IFN gamma modulation for cancer therapy is still unsuccessful due to its complex effects on various host cells. In this study, we found that treatment of Lewis lung carcinoma transplants with cisplatin often caused IFN gamma-dependent tumour vascular damage. IFN gamma induced endothelial glycolysis and lactate production, leading to enhanced endocytosis of vascular endothelial (VE)-cadherin and vessel leakage. We have also developed anti-IFN gamma nanoparticles coated with a clot-binding peptide CREKA (CREKA-lipo-anti-IFN gamma), which targets the fibrin-fibronectin complex that appears in the leaky site of damaged tumour blood vessels. Blocking IFN gamma activity in the leakage site of capillaries using nanoparticles rescued VE-cadherin distribution on the endothelial cellular surface, promoted blood vessel integrity, and improved drug delivery. In conclusion, IFN gamma blockade in capillary leak site protected tumour blood vessels from lactate-dependent VE-cadherin loss and enhanced drug delivery during chemotherapy, which provides a basis for tissue-specific IFN gamma blockade for tumour therapy.

Automated summary

This study found that treatment with cisplatin often caused IFN gamma-dependent tumor vascular damage. The researchers developed nanoparticles that targeted the leakage site of damaged tumor blood vessels and blocked IFN gamma activity, promoting blood vessel integrity and drug delivery.