CXCL12-targeted immunomodulatory gene therapy reduces radiation-induced fibrosis in healthy tissues

Paget, James T., Ward, Joseph A., McKean, Andrew R., Mansfield, David C., McLaughlin, Martin, Kyula-Currie, Joan N., Smith, Henry G., Roulstone, Victoria, Li, Chunhei, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291, Hardiman, Thomas, Grigoriadis, Anita, O'Brien Coon, Devin, Irshad, Sheeba, Melcher, Alan A., Harrington, Kevin J. and Khan, Aadil 2024. CXCL12-targeted immunomodulatory gene therapy reduces radiation-induced fibrosis in healthy tissues. Molecular Cancer Therapeutics 10.1158/1535-7163.MCT-23-0872 Item availability restricted.

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Abstract

Radiation-induced fibrosis (RIF) is a progressive pathology deleteriously impacting cancer survivorship. CXCL12 is an immune-stromal signal implicated in fibrosis and innate response. We hypothesised that modulation of CXCL12 would phenotypically mitigate RIF. CXCL12 expression was characterised in a rodent model of RIF and its expression modulated by the intravascular delivery of lentiviral vectors encoding small hairpin RNA to silence (LVShCXCL12) or overexpress (LVOeCXCL12) CXCL12. Multi-modal fibrotic outcomes were quantified, flow cytometry and Y-chromosome lineage-tracking studies performed to examine cellular recruitment and activation post-radiotherapy (post-RT). Whole-tissue RNA-seq was used to examine matrisomal response. MATBIII tumours were engrafted within tissues with differing levels of CXCL12 expression and tumoral response to RT evaluated. CXCL12 was upregulated in irradiated fibroblasts demonstrating DNA-damage post-RT and led to the recruitment of CD68+ macrophages. Silencing Cxcl12 with LVShCXCL12 demonstrated reduced RIF phenotype as a result of decreased macrophage recruitment. Transcriptomic profiling identified osteopontin (SPP1) as being highly differentially expressed in LVShCXCL12-treated tissues. Tumours growing in tissues devoid of CXCL12 expression responded better following RT due to reductions in peri-tumoural fibrosis as a result of decreased CXCL12 and OPN expression at the tumour/normal tissue interface. This was also associated with greater CD8+ T cell infiltration in tumours with less fibrosis. Antibody-mediated OPN blockade slowed tumour growth by increased intra-tumoral CD8+ T cell activation. The CXCL12/OPN axis is an important node of immune/matrisomal cross-talk in the development of fibrosis. Therapeutic manipulation of this axis may offer greater anti-tumour efficacy whilst also reducing adverse effects.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	American Association for Cancer Research
ISSN:	1535-7163
Date of First Compliant Deposit:	23 January 2025
Date of Acceptance:	4 December 2024
Last Modified:	23 Jan 2025 09:15
URI:	https://orca.cardiff.ac.uk/id/eprint/174943

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