Development of liposomal ODN to convert immunodeficiency to immunogenecity of pancreatic cancer tumor microenvironment

Pancreatic cancer is a high lethal malignancy. Surgery is the only curative method for it. However, more than sixty percent patients are diagnosed in late-stage disease, chemotherapy is the hope to treat patients. Disappointedly, the outcome is not good at present. Our series study showed that tumor associated macrophages in the pancreatic tumor microenvironment play an important role for progression of pancreatic cancer.
We proved that pancreatic cancer cells can skew M1 to M2 tumor associate macrophages, which convert the immunogenicity to immunosuppressive. The early infiltrating macrophage (M2)-derived tissue inhibitor of metallopeptidase 1 (TIMP-1) is the key factor in maintaining the ERKactiveDUSP2low cell population in a CD63-dependent manner. The ERKactiveDUSP2low cancer cells further exacerbate macrophage-mediated cancer malignancy, including loss of epithelial trait, increased lymphangiogenesis, and immune escape. Therefore, we further designed the STAT6-CYBB decoy ODN to prevent M2 formation in the pancreatic tumor microenvironment. Under the action of ODN, in vivo study showed the pancreatic tumor size was significantly reduced and there were many M1, NK cells, and CD8+ T cells filled in the tumor microenvironment. For augmentation the effect clinically, we further used liposome to embed the ODN to increase the penetration through the barrier of desmoplasia. The preliminary results were good, and it may be the hope to treat pancreatic cancer in future.