Intratumoral LIGHT Restores Pericyte Contractile Properties and Vessel Integrity
Anna Johansson-Percival,
Zhi-Jie Li,
Devina D. Lakhiani,
Bo He,
Xiao Wang,
Juliana Hamzah,
Ruth Ganss
Affiliations
Anna Johansson-Percival
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
Zhi-Jie Li
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
Devina D. Lakhiani
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
Bo He
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
Xiao Wang
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
Juliana Hamzah
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
Ruth Ganss
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
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.