CXCL12-Targeted Immunomodulatory Gene Therapy Reduces Radiation-Induced Fibrosis in Healthy Tissues.
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Authors
Paget, JT
Ward, JA
McKean, AR
Mansfield, DC
McLaughlin, M
Kyula-Currie, JN
Smith, HG
Roulstone, V
Li, C
Zhou, Y
Hardiman, T
Grigoriadis, A
O'Brien Coon, D
Irshad, S
Melcher, AA
Harrington, KJ
Khan, A
Ward, JA
McKean, AR
Mansfield, DC
McLaughlin, M
Kyula-Currie, JN
Smith, HG
Roulstone, V
Li, C
Zhou, Y
Hardiman, T
Grigoriadis, A
O'Brien Coon, D
Irshad, S
Melcher, AA
Harrington, KJ
Khan, A
Document Type
Journal Article
Date
2025-03-04
Date Accepted
2024-12-04
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 hypothesized that modulation of CXCL12 would phenotypically mitigate RIF. CXCL12 expression was characterized 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. Multimodal fibrotic outcomes were quantified, and flow cytometry and Y-chromosome lineage-tracking studies performed to examine cellular recruitment and activation after radiotherapy. Whole-tissue RNA sequencing was used to examine matrisomal response. MATBIII tumors were engrafted within tissues with differing levels of CXCL12 expression, and tumoral response to RT was evaluated. CXCL12 was upregulated in irradiated fibroblasts demonstrating DNA damage after radiotherapy, which 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 (OPN; SPP1) as being highly differentially expressed in LVShCXCL12-treated tissues. Tumors growing in tissues devoid of CXCL12 expression responded better after RT because of reductions in peritumoral fibrosis as a result of decreased CXCL12 and OPN expression at the tumor/normal tissue interface. This was also associated with greater CD8+ T-cell infiltration in tumors with less fibrosis. Antibody-mediated OPN blockade slowed tumor growth by increased intratumoral 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 antitumor efficacy while also reducing adverse effects.
Citation
Molecular Cancer Therapeutics, 2024, pp. OF1 - OF13
Source Title
Molecular Cancer Therapeutics
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1535-7163
eISSN
1538-8514
Collections
Research Team
Targeted Therapy
Trans Immunotherapy
Trans Immunotherapy