Combination Immunotherapy Enhances Serial Radiofrequency Ablation Induced Systemic Antitumor Immunity in Pancreatic Cancer

Abstract

Thermal ablation is increasingly used for local control of pancreatic ductal adenocarcinoma (PDAC), but its capacity to induce systemic antitumor immunity and the mechanisms limiting this response remain incompletely defined. Using a bilateral LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) flank tumor model, we show serial radiofrequency ablation (RFA) enhances local tumor control and induces a robust abscopal response. This effect was associated with increased activation of CD8 T cells and natural killer cells, and was abrogated by CD8 T cell depletion. Single-cell RNA sequencing revealed expansion of cytotoxic immune programs alongside induction of a CSF1R-driven myeloid response consistent with adaptive immune resistance. Although combinatorial blockade of PD-L1 and CD73 augmented systemic antitumor responses, and the addition of CSF1R inhibition in this context further enhanced both local and distant tumor control. These findings identify a CSF1R-dependent myeloid resistance program which constrains ablation-induced systemic immunity and demonstrate that rational combination immunotherapy can potentiate the systemic efficacy of tumor ablation in PDAC. STATEMENT OF TRANSLATIONAL RELEVANCERadiofrequency ablation is a local thermal therapy that induces tumor destruction and modulation of the tumor microenvironment used for treatment of many solid tumors, including pancreatic cancer. Serial thermal ablations induce a CD8+ T cells and NK cell antitumor immunological response; however, Nt5e (CD73) is increased in tumor cells, PD-1 is increased in CD8+ T cells, and serial ablations increase a CSF1R+ macrophage cluster in ablated tumors. Combinational targeting of CD73, PD-L1, and CSF1R alleviates CSF1R-dependent therapeutic resistance and enhances local and systemic tumor control. This study identifies targetable countervailing mechanisms to local ablation therapy and provides a rationale for combinatorial strategies integrating serial tumor ablation with systemic immunomodulatory agents. Future prospective studies should evaluate the influence of timing, dosage, and sequence of ablation on immune priming to improve clinical interventions in pancreatic cancer.