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Lookup NU author(s): Professor Helen ReevesORCiD, Professor Derek MannORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, and cases are predicted to rise dramatically over the next few years. Overcoming the immune microenvironment in HCC remains a challenge, and innate immune populations such as tumour-associated neutrophils can potentially impair the success of immunotherapy. Elucidating the mechanisms of neutrophil recruitment across liver endothelium could lead to new approaches to boost the efficacy of immunotherapy. CLEC14A is an endothelium-specific receptor regulating sprouting angiogenesis, upregulated in low shear environments. We found CLEC14A to be highly expressed in both HCC vessels and on vasculature during acute liver injury, leading us to hypothesise that CLEC14A may regulate neutrophil recruitment to the liver and HCC. We found that CLEC14A positively correlated with a neutrophil signature and infiltration in public datasets and surgically resected tissue from HCC. Spatial transcriptomics (ST) of CLEC14Ahigh- and CLEC14Alow-expressing tumours confirmed upregulation of myeloperoxidase in CLEC14Ahigh tumours and correlation with other shear-dependent markers but a negative correlation with vascular endothelial growth factor A. To build on our correlation studies, we explored the role of CLEC14A in neutrophil recruitment across liver endothelium. We undertook in vitro recruitment studies with flow-based human liver endothelial assays and in vivo models of neutrophil recruitment. Using siRNA knockdown of CLEC14A and specific blocking antibodies to CLEC14A, we found that CLEC14A knockdown blocked the firm adhesion of neutrophils to liver endothelium, but this was independent of its interaction with its known ligand MMRN2. Finally, we confirmed that Clec14a deficiency led to a significant reduction in neutrophil recruitment across the sinusoids in an ischaemia-reperfusion liver injury model. We unveil a link between the angiogenic receptor CLEC14A and neutrophil recruitment. Targeting of CLEC14A on tumour endothelium is potentially a new approach to regulating neutrophil infiltration in HCC. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Author(s): O'Rourke JM, Kavanagh D, O'Keeffe A, Savoye K, Yang K, Patten DA, Willoughby CE, Llovet JM, Neag G, Reeves HL, Hewett PW, Kalia N, Shah T, Ma YT, Hunter K, Flint J, McMurray JL, Cain O, Spill F, Mann DA, Naylor AJ, Heath V, Weston CJ, Bicknell R, Shetty S
Publication type: Article
Publication status: Published
Journal: Journal of Pathology
Year: 2026
Pages: Epub ahead of print
Online publication date: 01/06/2026
Acceptance date: 15/04/2026
Date deposited: 15/06/2026
ISSN (print): 0022-3417
ISSN (electronic): 1096-9896
Publisher: John Wiley and Sons Ltd
URL: https://doi.org/10.1002/path.70077
DOI: 10.1002/path.70077
Data Access Statement: RNA sequencing data are available through the Gene Expression Omnibus: GSE253962 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE253962
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