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Study findings suggest that SA-HFIRE causes a dynamic shift in tumor lymphatic and blood microvascular structures, potentially enhancing the adaptive immune response.

Sub-ablative high-frequency irreversible electroporation (SA-HFIRE) causes a dynamic shift in breast tumor lymphatic and blood microvascular structures, potentially enhancing the adaptive immune response, according to findings published in Annals of Biomedical Engineering.

“High-frequency irreversible electroporation (H-FIRE) is a minimally invasive local ablation therapy known to activate the adaptive immune system and reprogram the tumor microenvironment. Its predecessor, irreversible electroporation (IRE), transiently increases microvascular density and immune cell infiltration within the surviving non-ablated and non-necrotic tumor region, also known as the viable tumor region,” explained study author Jennifer Munson, PhD, of Fralin Biomedical Research Institute at VTC, and colleagues. “However, the impact of pulse electric field therapies on lymphatic vessels, crucial for T-cell fate and maturation, remains unclear.”

Using a murine breast cancer model, the researchers limited ablation coverage to investigate how SA-HFIRE alters blood and lymphatic vessels without directly killing them.

Multiple Findings

Key findings noted by the researchers included:

• Local and distal effects. SA-HFIRE triggered rapid, spatially variable remodeling of vasculature within the tumor, the adjacent mammary fat pad, and—more modestly—the tumor-draining lymph nodes (TDLNs).
• Transient angiogenesis. Platelet endothelial cell adhesion molecule-1 vessel density and luminal size rose briefly after treatment, likely reflecting reduced matrix compression as collagen cross-linking declined over seven days.
• Selective lymphatic changes. Lymphatic vessel density increased, yet lumen size remained stable, suggesting functional adaptation rather than pure enlargement. Podoplanin elevation hinted at fibroblast involvement, whereas classical vascular endothelial growth factors C (VEGFC) and A did not show an early surge.
• Immune-relevant biomarkers. Upregulation of secondary lymphoid-tissue chemokine (CCL21) and modest VEGFC gene expression within tumors—and their protein drainage to TDLNs—correlated with the extent of ablation, marking them as potential indicators of lymphatic activation.
• Lymph-node remodeling. TDLNs displayed enlarged high endothelial venules and higher lymphatic vessel endothelial hyaluronan receptor 1 staining in medullary lymphatics, morphological changes associated with T-cell trafficking during immune responses.

Enhancing the Adaptive Immune Response

“These findings suggest a dynamic shift in lymphatic and blood microvascular structures post-SA-HFIRE, potentially enhancing the adaptive immune response through CCL21- mediated lymphatic homing and subsequent lymph node microvascular remodeling,” the authors wrote, adding that collagen relaxation, altered fibroblast populations, and CCL21-mediated chemotaxis together create a microenvironment conducive to antigen presentation and adaptive immunity, even in the absence of early VEGF signaling.

“Future work will assess the immune and transport function of the microvasculature to inform experiments aimed at the application of adjuvant therapies during scenarios of tumor partial ablation,” the authors concluded.