An oligonucleotide-based microRNA inhibitor, CD5-2, upregulates the expression of the endothelial cell-specific junctional protein VE-cadherin, which normalizes blood vessel structure and function in the tumor microenvironment, alleviates some immunosuppressive effects (hypoxia, PD-L1 expression), supports tumor infiltration by CD8+ T cells, and enhances tumor control.
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. Lastly, 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.
Author Info: (1) Central Clinical School, Sydney Medical School, The University of Sydney, Centenary Institute. (2) Central Clinical School, Sydney Medical School, The University of Sydney, Cen
Author Info: (1) Central Clinical School, Sydney Medical School, The University of Sydney, Centenary Institute. (2) Central Clinical School, Sydney Medical School, The University of Sydney, Centenary Institute. (3) Central Clinical School, Sydney Medical School, The University of Sydney, Centenary Institute. (4) Central Clinical School, Sydney Medical School, The University of Sydney, ANZAC Research Institute. (5) Central Clinical School, Sydney Medical School, The University of Sydney, Centenary Institute. (6) Centre for Medical Research, The University of Western Australia, Harry Perkins Institute. (7) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute. (8) Origins of Cancer Laboratory, Centenary Institute. (9) Vascular Immunology Unit, the University of Sydney. (10) Radiation Oncology, Steele Lab for Tumor Biology. (11) Mirrx Therapeutics. (12) Department of Vascular Biology, IFOM, FIRC Institute of Molecular Oncology. (13) Centenary Institute, University of Sydney. (14) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute. (15) Harry Perkins Institute of Medical Research. (16) Vascular Biology, Centenary Institute. (17) Central Clinical School, Sydney Medical School, The University of Sydney, Centenary Institute j.gamble@centenary.org.au.
