Local Release of TGF-ß Inhibitor Modulates Tumor-Associated Neutrophils and Enhances Pancreatic Cancer Response to Combined Irreversible Electroporation and Immunotherapy

Pancreatic cancer is a deadly disease with little response to standard therapies. Irreversible electroporation (IRE) has emerged as a novel ablative technique for the clinical treatment of pancreatic cancer. Combinations of IRE and immunotherapies, including anti-programmed death 1 (alpha PD1) immune checkpoint blockade, have shown promising efficacy in both preclinical and clinical studies. However, tumor recurrence remains an obstacle that needs to be overcome. It herein is shown that IRE induces a substantial infiltration of neutrophils into pancreatic tumors. These neutrophils are then polarized into a protumor phenotype by immunosuppressive cues, in particular transforming growth factor beta (TGF-beta). Using glutathione-responsive degradable mesoporous silica nanoparticles loaded with SB525334, an inhibitor of TGF-beta 1 receptor, it is demonstrated that local inhibition of TGF-beta within the tumor microenvironment promotes neutrophil polarization into an antitumor phenotype, enhances pancreatic cancer response to combined IRE and alpha PD1 therapy, and induces long-term antitumor memory. The therapeutic efficacy is also attributed to tumor infiltration by CD8(+) cytotoxic T cells, depletion of regulatory T cells, and maturation of antigen-presenting dendritic cells. Thus, modulating neutrophil polarization with nanomedicine is a promising strategy for treating pancreatic cancer.

Automated summary

IRE combined with immunotherapy has shown promising efficacy in treating pancreatic cancer. Local inhibition of TGF-beta promotes neutrophil polarization into an antitumor phenotype and enhances treatment response.