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EMBO Mol Med. 2019 Dec;11(12):e10923. doi: 10.15252/emmm.201910923. Epub 2019 Nov 11.

Immune-mediated ECM depletion improves tumour perfusion and payload delivery.

Author information

1
Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia.
2
Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
3
Telethon Kids Institute, Subiaco, WA, Australia.
4
Centre for Microscopy, Characterisation & Analysis, The University of Western Australia, Perth, WA, Australia.
5
Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, WA, Australia.
6
Department of Biomedical Engineering, University of California Davis, Davis, CA, USA.
7
Sir Charles Gairdner Hospital, Perth, WA, Australia.
8
PathWest Laboratory Medicine, QE2 Medical Centre, Perth, WA, Australia.

Abstract

High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.

KEYWORDS:

extracellular matrix; immune cells; peptide; solid tumour; tumour necrosis factor alpha

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