CXCL12-Targeted Immunomodulatory Gene Therapy Reduces Radiation-Induced Fibrosis in Healthy Tissues

Area of Science:

• Oncology
• Immunology
• Fibrosis Research

Background:

• Radiation-induced fibrosis (RIF) is a significant complication impacting cancer survivors.
• CXCL12 is an immune-stromal factor involved in fibrotic processes.

Purpose of the Study:

• To investigate the role of CXCL12 in RIF.
• To determine if modulating CXCL12 can mitigate RIF and impact anti-tumor responses.

Main Methods:

• Characterized CXCL12 expression in a rodent RIF model.
• Utilized lentiviral vectors to silence (LVShCXCL12) or overexpress (LVOeCXCL12) CXCL12.
• Quantified fibrotic outcomes, performed flow cytometry, lineage-tracking, and RNA sequencing.
• Evaluated tumor response to radiotherapy (RT) in tissues with modulated CXCL12 levels.

Main Results:

• CXCL12 upregulation in irradiated fibroblasts correlated with CD68+ macrophage recruitment.
• Silencing CXCL12 reduced RIF and macrophage infiltration.
• Transcriptomic analysis identified osteopontin (OPN) as differentially expressed.
• Reduced CXCL12 and OPN expression decreased peritumoral fibrosis, enhancing CD8+ T-cell infiltration and anti-tumor response.
• OPN blockade improved intratumoral CD8+ T-cell activation and slowed tumor growth.

Conclusions:

• The CXCL12/OPN axis is crucial for immune-stromal crosstalk in fibrosis development.
• Therapeutic targeting of this axis holds potential for reducing RIF and improving anti-tumor efficacy.