Iatrogenic injury to the healthy ureter during ureteroscope-guided ablation of malignant or nonmalignant disease can result in ureteral stricture. Transforming growth factor (TGF)-β₁-mediated scar formation is considered to underlie ureteral stricture, but the cellular sources of this cytokine and the sequelae preceding iatrogenic stricture formation are unknown. Using a swine model of ureteral injury with irreversible electroporation (IRE), we evaluated the cellular sources of TGF-β₁ and scar formation at the site of injury and examined in vitro whether the effects of TGF-β₁ could be attenuated by pirfenidone. We observed that proliferation and α-smooth muscle actin expression by fibroblasts were restricted to injured tissue and coincided with proliferation of macrophages. Collagen deposition and scarring of the ureter were associated with increased TGF-β₁ expression in both fibroblasts and macrophages. Using in vitro experiments, we demonstrated that macrophages stimulated by cells that were killed with IRE, but not LPS, secreted TGF-β₁, consistent with a wound healing phenotype. Furthermore, using 3T3 fibroblasts, we demonstrated that stimulation with paracrine TGF-β₁ is necessary and sufficient to promote differentiation of fibroblasts and increase collagen secretion. In vitro, we also showed that treatment with pirfenidone, which modulates TGF-β₁ activity, limits proliferation and TGF-β₁ secretion in macrophages and scar formation-related activity by fibroblasts. In conclusion, we identified wound healing-related macrophages to be an important source of TGF-β₁ in the injured ureter, which may be a paracrine source of TGF-β₁ driving scar formation by fibroblasts, resulting in stricture formation.

Background: This study investigated the sparing of the extracellular matrix (ECM) and blood vessels at the site of lung irreversible electroporation (IRE), and its impact on postablation T cell and macrophage populations. Materials and Methods: Normal swine ( n = 8) lung was treated with either IRE or microwave ablation (MWA), followed by sacrifice at 2 and 28 days (four animals/timepoint) after treatment. En bloc samples of ablated lung were stained for blood vessels (CD31), ECM proteins (Collagen, Heparan sulfate, and Decorin), T cells (CD3), and macrophages (Iba1). Stained slides were analyzed with an image processing software (ImageJ) to count the number of positive staining cells or the percentage area of tissue staining for ECM markers, and the statistical difference was evaluated with Student's t -test. Results: Approximately 50% of the blood vessels and collagen typically seen in healthy lung were evident in IRE treated samples at Day 2, with complete destruction within MWA treated lung. These levels increased threefold by Day 28, indicative of post-IRE tissue remodeling and regeneration. Decorin and Heparan sulfate levels were reduced, and it remained so through the duration of observation. Concurrently, numbers of CD3 ⁺ T cells and macrophages were not different from healthy lung at Day 2 after IRE, subsequently increasing by 2.5 and 1.5-fold by Day 28. Similar findings were restricted to the peripheral inflammatory rim of MWA samples, wherein the central necrotic regions remained acellular through Day 28. Conclusion: Acute preservation of blood vessels and major ECM components was observed in IRE treated lung at acute time points, and it was associated with the increased infiltration and presence of T cells and macrophages, features that were spatially restricted in MWA treated lung.

Adoptive cell therapy with chimeric antigen receptors (CAR) T cells has proven effective for hematologic malignancies, but success in solid tumors has been impeded by poor intratumoral infiltration, exhaustion of effector cells from antigen burden, and an immunosuppressive tumor microenvironment. Results from recent clinical trials and preclinical studies lend promising evidence of locoregional approaches for CAR T cell delivery, priming the tumor microenvironment, and performing adjuvant therapies that sustain T cell activity. Interventional oncology is a subspeciality of interventional radiology where imaging guidance is used to perform percutaneous and catheter-directed procedures for localized, non-surgical therapy or interrogation of solid tumors. Interventional oncology provides unique synergies with immunotherapy, which has been well-studied to improve treatment efficacy while reducing toxicities associated with systemic treatment. Besides aiding in CAR T cell delivery, priming, or the stimulation of the tumor microenvironment to promote effector survival and function, interventional oncology can also aid in the monitoring of treatment response through selective, multiplex tumor sampling and catheter-based venous sampling. This review presents an overview of interventional oncology, its various procedures, and its potential for advancing CAR T cell immunotherapy of solid tumors.