Immune‐mediated ECM depletion improves tumour perfusion and payload delivery. Issue 12 (11th November 2019)

• Record Type: Journal Article
• Authors: Yeow, Yen Ling; Kotamraju, Venkata Ramana; Wang, Xiao; Chopra, Meenu; Azme, Nasibah; Wu, Jiansha; Schoep, Tobias D; Delaney, Derek S; Feindel, Kirk; Li, Ji; Kennedy, Kelsey M; Allen, Wes M; Kennedy, Brendan F; Larma, Irma; Sampson, David D; Mahakian, Lisa M; Fite, Brett Z; Zhang, Hua; Friman, Tomas; Mann, Aman P; Aziz, Farah A; Kumarasinghe, M Priyanthi; Johansson, Mikael; Ee, Hooi C; Yeoh, George; Mou, Lingjun; Ferrara, Katherine W; Billiran, Hector; Ganss, Ruth; Ruoslahti, Erkki; Hamzah, Juliana;
• Is Part Of: EMBO molecular medicine. Volume 11:Issue 12(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-11-11
• Subjects: extracellular matrix -- immune cells -- peptide -- solid tumour -- tumour necrosis factor alpha; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201910923
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: This study establishes a new approach to treat solid tumours by immune modulation and ECM depletion. The developed agent, TNFα‐CSG, has dual capacity as an immunotherapeutic and ECM reducing agent which improves tumour perfusion and drug delivery. Extracellular matrix (ECM) targeting peptide, CSG, specifically recognises the ECM in multiple types of murine and human tumours. CSG targeting effectively delivers TNFα into tumours and elicits immune cell infiltration into the ECM. Immune‐mediated ECM degradation by a cocktail of proteases reduces tumour stiffness and decompression of tumour blood vessels, and enhances tumour perfusion. TNFα‐CSG treatment sensitizes tumours for enhanced uptake of diagnostic nanoparticles. The anti‐tumour effects of TNFα‐CSG are primarily mediated by T cells. Abstract : This study establishes a new approach to treat solid tumours by immune modulation and ECM depletion. The developed agent, TNFα‐CSG, has dual capacity as an immunotherapeutic and ECM reducing agent which improves tumour perfusion and drug delivery.