Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate

Frontiers in Immunology

Immunology

Geoffrey W. McCaughan¹  Ken Liu¹  Glen Lockwood²  Yang Zhao³  Ka Ka Ting³  Jinbiao Chen³  Jade Boland³  Mathew A. Vadas⁴  Jennifer R. Gamble⁴  Catriona McKenzie⁵  James Kench⁵ 

[1] AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia;Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia;Centenary Institute, University of Sydney, Sydney, NSW, Australia;Biogerontology Group, ANZAC Research Institute, Sydney, NSW, Australia;Centenary Institute, University of Sydney, Sydney, NSW, Australia;Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia;Centenary Institute, University of Sydney, Sydney, NSW, Australia;New South Wales Health Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia;

关键词: hepatocellular carcinoma;    angiogenesis;    vascular normalization;    immunotherapy;    hypoxia;   

DOI  :  10.3389/fimmu.2023.1245708

 received in 2023-06-23, accepted in 2023-09-01,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionLiver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial-specific cadherin. The combination of a vasoactive medication with inhibition of immune checkpoints such as programmed cell death protein 1 (PD1) has been shown to be effective in treating liver cancer in humans. We aimed to study the effect of CD5-2 combined with checkpoint inhibition (using an antibody against PD1) on liver tumor growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumor mouse model.MethodsWe first analyzed human miR-27a and VE-Cadherin expression data from The Cancer Genome Atlas for hepatocellular carcinoma. CD5-2 and/or anti-PD1 antibody were given to the DEN-treated mice from age 7-months until harvest at age 9-months. Tumor and non-tumor liver tissues were analyzed using histology, immunohistochemistry, immunofluorescence and scanning electron microscopy.ResultsHuman data showed high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumors (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumor number. Histologically, tumors in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumor hypoxia compared to non-CD5-2-treated mice. Only tumors in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favorable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumors from other groups.DiscussionCD5-2 normalized tumor vasculature and reduced hypoxia in DEN-induced liver tumors. CD5-2 plus anti-PD1 antibody reduced liver tumor size possibly by altering the immune infiltrate to a more immunosupportive one.

【 授权许可】

Unknown   
Copyright © 2023 Liu, Chen, Zhao, Boland, Ting, Lockwood, McKenzie, Kench, Vadas, Gamble and McCaughan