Work

Irreversible electroporation targets both innate and adaptive anti-tumor immune mechanisms in vivo 4122

Year: 2025

Type: article

Abstract: Description Focal tumor therapies including irreversible electroporation (IRE) are of clinical interest for ablation of solid tumors with difficult surgical resection profiles. The mechanism by which IRE enhances anti-tumor CD8+ T cell responses is poorly understood. Using injectable KPC pancreatic tumor cells we found that compared to high dose treatment, intermediate IRE doses promoted increased numbers of total and migratory type 1 and 2 dendritic cells (XCR1+ cDC1 and Sirp1+ cDC2), CX3CR1+ monocytes, and F480+ macrophages in tumor-draining lymph nodes (tdLN) 1-2 days following treatment, despite inducing similar levels of cell death in the tumor mass. Intermediate IRE dosing was associated with loss of prominent intratumoral CD206+/Arginase+ macrophages and emergence of rare CD206 low/iNOS+ macrophages, suggesting a pro-inflammatory conversion. In vitro and in vivo assays showed that exposure to IRE-generated tumor cell lysates led to increased CD86 expression and phagocytic antigen uptake in tdLN DCs, as well as OVA-specific T-cell proliferation. Timed depletion of cDC1 in vivo blunted IRE-induced Ag-specific T cell responses and eliminated the boost of endogenous CD8+ T cells in a model of combinatorial IRE/anti-CTLA-4 tumor therapy. These results demonstrate a key role for cDC1 in CD8+ T cell responses associated with IRE, and reveal additional aspects of the immune landscape that can be further leveraged to optimize IRE dosing and timing for effective anti-tumor therapy. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1843