Immune‐mediated ECM depletion improves tumour perfusion and payload delivery

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.

Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

“…Using cytokine profiling, we demonstrated that PFD significantly depleted the secretion of cancer-and invasion-promoting cytokines, particularly IL8, CCL17, and TNF-β. Many studies highlighted the critical role of these factors in the interaction of the carcinomastromal cell and ECM deposition toward the induction of an invasive TME and activation of EMT and stemness [6,7,61,62].…”

Enhanced Detection of Desmoplasia by Targeted Delivery of Iron Oxide Nanoparticles to the Tumour-Specific Extracellular Matrix

“…We have recently reported the discovery of a peptide, CSG (CSGRRSSKC) that binds specifically to the laminin-nidogen-1 complex of the ECM in mouse and human breast, pancreas and liver tumours [49]. We have shown that CSG fused to a cytokine, TNFα, acts as a delivery agent allowing for specific binding of TNFα to tumour ECM, triggering effective immune-mediated anti-tumour effects [49].…”

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…Large number of such molecules carry either anti-or pro-inflammatory protein in hopes of deciphering immune response [32,[78][79][80][81][82][83][84]. Recently, a homing peptide targeting tumor ECM delivered tumor necrosis factor-α (TNFα) to ECM rich regions in tumors and caused immune cell infiltration and subsequent immune cell-induced ECM breakage [79]. Theoretically, similar approaches inducing "immunological reaction towards connective tissue" could be applied to situations where scarring or fibrosis has ensued, and the breakage of the fibrosis is desirable without side effects in the rest of the body.…”