Abstract:
:T-cell infiltration of solid tumors is associated with improved prognosis and favorable responses to immunotherapy. Mechanisms that enable tumor infiltration of CD8+ T cells have not been defined, nor have drugs that assist this process been discovered. Here we address these issues with a focus on VE-cadherin, a major endothelial cell-specific junctional protein that controls vascular integrity. A decrease in VE-cadherin expression is associated with tumor pathology. We developed an oligonucleotide-based inhibitor (CD5-2), which disrupted the interaction of VE-cadherin with its regulator miR-27a, resulting in increased VE-cadherin expression. Administration of CD5-2 in tumor-bearing mice enhanced expression of VE-cadherin in tumor endothelium, activating TIE-2 and tight junction pathways and normalizing vessel structure and function. CD5-2 administration also enhanced tumor-specific T-cell infiltration and spatially redistributed CD8+ T cells within the tumor parenchyma. Finally, CD5-2 treatment enhanced the efficacy of anti-PD-1 blocking antibody. Our work establishes a role for VE-cadherin in T-cell infiltration in tumors and offers a preclinical proof of concept for CD5-2 as a therapeutic modifier of cancer immunotherapy via effects on the tumor vasculature. Cancer Res; 77(16); 4434-47. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Zhao Y,Ting KK,Li J,Cogger VC,Chen J,Johansson-Percival A,Ngiow SF,Holst J,Grau G,Goel S,Muller T,Dejana E,McCaughan G,Smyth MJ,Ganss R,Vadas MA,Gamble JRdoi
10.1158/0008-5472.CAN-16-3129subject
Has Abstractpub_date
2017-08-15 00:00:00pages
4434-4447issue
16eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-16-3129journal_volume
77pub_type
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