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.
Highlights
The microenvironment of solid tumors has increasingly been recognized as one of the major drivers of tumor progression and resistance to therapy [1]
The experiments were repeated with three independently synthesized batches of CD5-2, and in a doubleblind experimental controlled situation, and the results show a significant inhibition of tumor growth (42% decrease in the tumor volume, n 1⁄4 4; Fig. 1C)
We have developed a first-in-class drug, CD5-2, that is unique in its design
Summary
The microenvironment of solid tumors has increasingly been recognized as one of the major drivers of tumor progression and resistance to therapy [1]. The. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Alterations in the microenvironment are strongly linked with abnormalities in tumor blood vessels, which are often structurally disordered dilated and tortuous with low perivascular coverage. Abnormal tumor blood vessels contribute to the immune suppressive characteristics of the tumor microenvironment Human tumors that fail to respond to therapy suffer from the exclusion of T cells from the TME and especially in the hypoxic core of the tumors [9]. As such the central infiltration of T cells is almost universally a favorable prognostic marker in humans [10]. Given the major role that the vasculature plays in controlling immune cell infiltration, restoring the integrity of the tumor vasculature is essential for effective anticancer therapy
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