Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2041754 | Cell Reports | 2015 | 12 Pages |
•LIGHT targeting into tumors normalizes the vasculature and improves therapy•Vascular integrity is restored by inducing pericyte contractility•LIGHT triggers a peri-vascular signaling cascade involving macrophages and TGF-β•LIGHT-RGR effects are Rho kinase-dependent and restricted to the vascular bed
SummaryNormalization 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.
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