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Transient Lymphatic Remodeling Follows Sub-Ablative High-Frequency Irreversible Electroporation Therapy in a 4T1
Savieay Esparza1,2, Edward Jacobs2,3, Jennifer H Hammel1,2
1Fralin Biomedical Research Institute at Virginia Tech-Carilion, Room 1210, 4 Riverside Circle, Roanoke, VA, 24016, USA.
Annals of Biomedical Engineering
|February 25, 2025
Summary
Sub-ablative high-frequency irreversible electroporation (SA-HFIRE) therapy transiently remodels blood and lymphatic vessels within tumors and surrounding tissues. This vascular remodeling, particularly increased lymphatic vessel density, may enhance immune responses by promoting T-cell homing to lymph nodes.
Area of Science:
- Oncology
- Immunology
- Biomedical Engineering
Background:
- High-frequency irreversible electroporation (H-FIRE) is a local ablation therapy that activates the immune system and reprograms the tumor microenvironment.
- Previous studies on irreversible electroporation (IRE) show increased microvascular density and immune cell infiltration in viable tumor regions.
- The effect of pulse electric field therapies on lymphatic vessels, crucial for T-cell function, is not well understood.
Purpose of the Study:
- To investigate the impact of sub-ablative H-FIRE (SA-HFIRE) on lymphatic and blood microvascular remodeling.
- To analyze temporal and spatial vascular changes in the viable tumor, peritumoral fat pad, and tumor-draining lymph node.
- To explore the role of specific genes (CCL21, CXCL2, VEGFA, VEGFC) in SA-HFIRE-induced vascular remodeling.
Main Methods:
- Utilized the 4T1 mammary mouse model for SA-HFIRE treatment.
- Conducted temporal and spatial analysis of vascular changes via histological examination.
- Performed gene expression analysis (CCL21, CXCL2, VEGFA, VEGFC) and protein quantification (CCL21).
Main Results:
- Observed a transient increase in blood vessel density on Day 1 post-treatment.
- Detected a spike in lymphatic vessel density in the viable tumor region on Day 3 post-treatment.
- Noted increased lymphatic vessel density in the peripheral fat pad, with minimal lymph node remodeling within 3 days.
- Gene expression showed elevated CCL21 and CXCL2 on Day 1; VEGFA/VEGFC did not significantly contribute to remodeling.
- CCL21 protein levels in lymph nodes correlated with tumor gene expression.
Conclusions:
- SA-HFIRE induces dynamic shifts in lymphatic and blood microvascular structures.
- The observed vascular remodeling, particularly CCL21-mediated lymphatic changes, may enhance adaptive immune responses via improved T-cell homing.
- Further research is needed to assess the immune and transport functions of the vasculature to optimize adjuvant therapy timing after partial tumor ablation.
