title: Intratumoral LIGHT Restores Pericyte Contractile Properties and Vessel Integrity.
abstract: Normalization of the tumor vasculature is an emerging concept shown to improve anti-cancer therapy. However, there are currently no clinical interventions that effect long-lasting normalization. Here, we have developed a strategy for normalization by specific intratumoral delivery of LIGHT/TNFSF14. Importantly, normalization occurs by induced expression of contractile markers in intratumoral pericytes, which in turn re-establishes tight pericyte-vessel alignment. Restoring vessel integrity improves tumor perfusion and acts as adjuvant to chemo- and immunotherapy. Mechanistically, intratumoral LIGHT induces pericyte differentiation and normalization via Rho kinase signaling. Minute amounts of LIGHT act in a paracrine fashion to trigger an amplifying cascade involving transforming growth factor β (TGF-β) from peri-vascular macrophages. That these effects can be reproduced by adoptive transfer of LIGHT-stimulated macrophages alone demonstrates their central role in regulating pericyte differentiation. Our findings highlight a crucial role of pericyte contractile properties in vascular normalization, effected by macrophage signaling, thus providing so far unexplored anti-cancer opportunities.
authors.affiliation: Vascular Biology and Stromal Targeting, Harry Perkins Institute of Medical Research, The University of Western Australia, Centre for Medical Research, Nedlands, Western Australia 6009, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Johansson-Percival
authors.affiliation: Vascular Biology and Stromal Targeting, Harry Perkins Institute of Medical Research, The University of Western Australia, Centre for Medical Research, Nedlands, Western Australia 6009, Australia.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Li
authors.affiliation: Vascular Biology and Stromal Targeting, Harry Perkins Institute of Medical Research, The University of Western Australia, Centre for Medical Research, Nedlands, Western Australia 6009, Australia.
authors.forename: Devina D
authors.initials: DD
authors.lastname: Lakhiani
authors.affiliation: Vascular Biology and Stromal Targeting, Harry Perkins Institute of Medical Research, The University of Western Australia, Centre for Medical Research, Nedlands, Western Australia 6009, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: He
authors.affiliation: Targeted Drug Delivery, Imaging, and Therapy, Harry Perkins Institute of Medical Research, The University of Western Australia, Centre for Medical Research, Nedlands, Western Australia 6009, Australia.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Targeted Drug Delivery, Imaging, and Therapy, Harry Perkins Institute of Medical Research, The University of Western Australia, Centre for Medical Research, Nedlands, Western Australia 6009, Australia.
authors.forename: Juliana
authors.initials: J
authors.lastname: Hamzah
authors.affiliation: Vascular Biology and Stromal Targeting, Harry Perkins Institute of Medical Research, The University of Western Australia, Centre for Medical Research, Nedlands, Western Australia 6009, Australia. Electronic address: ganss@perkins.uwa.edu.au.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ganss
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D020286:Pericytes / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism*
chemical_list: C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14