Pulsed Electric Field Ablation Reprograms Tumor Immunity and Stimulates Germinal Center Formation in Tertiary Lymphoid Structures in Patients with Non-Small Cell Lung Cancer

Purpose: This treat-and-resect clinical study evaluated a specialized form of pulsed electric field (PEF) ablation’s potential to modulate antitumor immunity in early-stage non-small cell lung cancer (NSCLC). Tertiary lymphoid structures (TLS) are lymphoid aggregates that recruit immune cells into the tumor microenvironment (TME) and serve as immunity-generating neighborhoods. TLS with germinal centers (GC) have strong prognostic value in most cancers and promote tumor control and responsiveness to immune-based therapies, but no commercially available therapeutics induce their formation. The Aliya System is a proprietary electrosurgical technology that delivers microsecond electrical pulses to tissue, achieving tumor clearance while maintaining stromal architecture. Patients and Methods: Treatment group patients received ablation immediately after diagnostic biopsy versus a biopsy-only control group. Herein we report on exploratory endpoints examining immune modulation in blood and tumor samples collected from patients in both groups. Results: Histopathological assessments revealed the presence of TLS with GC in resected tumors. Tissue cytokine assessments and single-cell RNA sequencing demonstrated upregulation of cytokines capable of recruiting and organizing TLS-associated lymphocytes, including CXCL13, and significant increases in GC-related immune populations, including class-switched memory B cells and plasma cells in ablated tumors versus pre-ablation biopsies. Ablation group patients had more tumors containing TLS with GC (47%) vs. control (24%). Ablation group patients exhibited enhanced systemic immunity, with increased serum HMGB1 and circulating cytotoxic T cells. Conclusions: This specialized PEF may orchestrate multiple simultaneous changes that promote a more immunologically active TME and represent a new approach for improving immunotherapeutic regimen responses in NSCLC patients.