Immunogenic death of hepatocellular carcinoma cells in mice expressing caspase-resistant ROCK1 is not replicated by ROCK inhibitors

Naylor, G., Julian, L., Watson-Bryce, S., Mullin, M., Nibbs, R. J. and Olson, M. F. (2022) Immunogenic death of hepatocellular carcinoma cells in mice expressing caspase-resistant ROCK1 is not replicated by ROCK inhibitors. Cancers, 14(23), 5943. (doi: 10.3390/cancers14235943) (PMID:36497425) (PMCID:PMC9740421)

Abstract

The morphological changes during apoptosis help facilitate “immunologically silent” cell death. Caspase cleavage of the ROCK1 kinase results in its activation, which drives the forceful contraction of apoptotic cells. We previously showed that when ROCK1 was mutated to render it caspase-resistant, there was greater liver damage and neutrophil recruitment after treatment with the hepatotoxin diethylnitrosamine (DEN). We now show that acute DEN-induced liver damage induced higher levels of pro-inflammatory cytokines/chemokines, indicative of immunogenic cell death (ICD), in mice expressing non-cleavable ROCK1 (ROCK1nc). Hepatocellular carcinoma (HCC) tumours in ROCK1nc mice had more neutrophils and CD8+ T cells relative to mice expressing wild-type ROCK1, indicating that spontaneous tumour cell death also was more immunogenic. Since ICD induction has been proposed to be tumour-suppressive, the effects of two distinct ROCK inhibitors on HCC tumours was examined. Both fasudil and AT13148 significantly decreased tumour numbers, areas and volumes, but neither resulted in greater numbers of neutrophils or CD8+ T cells to be recruited. In the context of acute DEN-induced liver damage, AT13148 inhibited the recruitment of dendritic, natural killer and CD8+ T cells to livers. These observations indicate that there is an important role for ROCK1 cleavage to limit immunogenic cell death, which was not replicated by systemic ROCK inhibitor administration. As a result, concomitant administration of ROCK inhibitors with cancer therapeutics would be unlikely to result in therapeutic benefit by inducing ICD to increase anti-tumour immune responses.

• Item Type: Articles
• Additional Information: Funding: This research was funded by the Canadian Institutes of Health Research (PJT-169106), Canada Research Chairs Program (950-231665), and by Cancer Research UK institutional funding to the CRUK Beatson Institute (A10419, A17196) and to the Olson lab (A18276).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nibbs, Professor Rob and Naylor, Gregory and Mullin, Mrs Margaret and Olson, Professor Michael
• Authors: Naylor, G., Julian, L., Watson-Bryce, S., Mullin, M., Nibbs, R. J., and Olson, M. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Cancers
• Publisher: MDPI
• ISSN: 2072-6694
• ISSN (Online): 2072-6694
• Published Online: 30 November 2022
• Copyright Holders: Copyright © 2022 by the authors
• First Published: First published in Cancers 14(23): 5943
• Publisher Policy: Reproduced under a Creative Commons License