AUTHOR=Liu Ken , Chen Jinbiao , Zhao Yang , Boland Jade , Ting Ka Ka , Lockwood Glen , McKenzie Catriona , Kench James , Vadas Mathew A. , Gamble Jennifer R. , McCaughan Geoffrey W. 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1245708

DOI=10.3389/fimmu.2023.1245708

ISSN=1664-3224

ABSTRACT=Liver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalisation of tumour 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 tumour growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumour mouse model. We first analysed human data from The Cancer Genome Atlas for hepatocellular carcinoma and found high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. CD5-2 and/or anti-PD1 antibody were given to the mice from age 7-months until harvest at age 9-months. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumours (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumour number. Histologically, tumours in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumour hypoxia compared to non-CD5-2-treated mice. Only tumours in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favourable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumours from other groups. Thus, CD5-2 normalised tumour vasculature and reduced hypoxia in DEN-induced liver tumours. CD5-2 plus anti-PD1 antibody reduced liver tumour size possibly by altering the immune infiltrate to a more immunosupportive one.