Combination Doxorubicin and Interferon-α Therapy Stimulates Immunogenicity of Murine Pancreatic Cancer Panc02 Cells via Up-regulation of NKG2D ligands and MHC Class ?

摘要

Background: Pancreatic adenocarcinoma is a malignant gastrointestinal cancer with significant morbidity andmortality. Despite severe side effects of chemotherapy, the use of immunotherapy combined with chemotherapy hasemerged as a common clinical treatment. In this study, we investigated the efficacy of the combined doxorubicinand interferon-α (IFN-α) therapy on murine pancreatic cancer Panc02 cells in vitro and in vivo and underlyingmechanisms. Materials and Methods: A Panc02-bearing mouse model was established to determine whetherdoxorubicin and interferon-α (IFN-α) could effectively inhibit tumor growth in vivo. Cytotoxicity of naturalkiller (NK) cells and cytotoxic T lymphocytes (CTLs) was evaluated using a standard LDH release assay. Toevaluate the relevance of NK cells and CD8 T cells to the combination therapy-mediated anti-tumor effects,they were depleted in tumor-bearing mice by injecting anti-asialo-GM-1 antibodies or anti-CD8 antibodies,respectively. Finally, the influence of doxorubicin+interferon-α (IFN-α) on the ligands of NK and T cells wasassessed by flow cytometry. Results: The combination therapy group demonstrated a significant inhibition ofgrowth of Panc02 in vivo, resulting from activated cytotoxicity of NK cells and CTLs. Depleting CD8 T cells orNK cells reduced the anticancer effects mediated by immunochemotherapy. Furthermore, the doxorubicin+IFN-atreatment increased the expression of major histocompatibility complex class ? (MHC ?) and NKG2D ligands onPanc02 cells, suggesting that the combined therapy may be a potential strategy for enhancing immunogenicityof tumors. All these data indicate that the combination therapy using doxorubicin and interferon-α (IFN-α) maybe a potential strategy for treating pancreatic adenocarcinoma.