ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2023; 19(5):1490-1508. doi:10.7150/ijbs.78248 This issue Cite
Research Paper
IFNγ blockade in capillary leak site improves tumour chemotherapy by inhibiting lactate-induced endocytosis of vascular endothelial-cadherins
1. Medical Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
2. Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
* These authors have contributed equally to this work and share first authorship.
Abstract
IFNγ has long been recognised as a key mediator of tumour immunity and angiostasis. However, IFNγ 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 IFNγ-dependent tumour vascular damage. IFNγ induced endothelial glycolysis and lactate production, leading to enhanced endocytosis of vascular endothelial (VE)-cadherin and vessel leakage. We have also developed anti-IFNγ nanoparticles coated with a clot-binding peptide CREKA (CREKA-lipo-anti-IFNγ), which targets the fibrin-fibronectin complex that appears in the leaky site of damaged tumour blood vessels. Blocking IFNγ 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, IFNγ 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 IFNγ blockade for tumour therapy.
Keywords: IFNγ blockade, vascular endothelial-cadherin, lactate, capillary leak, chemotherapy.
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