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

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)