Cancer Cells Containing Nanoscale Chemotherapeutic Drugs Generate Antiovarian Cancer-specific CD4(+) T Cells in Peritoneal Space

Abstract

Owing to the poor prognosis of patients with ovarian cancer, new treatment strategies immediately need to be developed. Although several immunotherapeutic approaches have been examined for the treatment of advanced stage ovarian cancer, their implementation in clinical practice remains low. We previously showed doxorubicin-treated murine ovarian cancer cells [murine ovarian surface epithelial cells (MOSECs)] are able to deliver drug to adjacent cells in vivo to eradicate tumor cells. In this study, we hypothesized that irradiated tumor cell treated with anticancer drugs may kill other cancer cell by cell to cell contact and also by generating antitumor immune responses. The MOSECs treated with anticancer drugs (doxorubicin and cisplatin) died through apoptosis, and this was increased in accordance with the dose of drug. The cleaved caspase-3 expression was significantly increased in the MOSECs coexposed with doxorubicin and cisplatin. Anticancer drug-treated MOSECs generated MOSEC-specific CD4(+) T-cell immune responses. Bone marrow-derived dendritic cells expressed upregulated IL-12p40 mRNA but IL-6 and IL-10 mRNA downregulated after coculture with MOSECs cotreated with doxorubicin and cisplatin. Furthermore, the mice vaccinated with MOSECs cotreated with doxorubicin and cisplatin had enhanced antitumor immunity and prolonged survival. We also observed that CD4(+) T cells and natural killer cells are essential for the antitumor immunity generated by vaccination with anticancer drug-loaded MOSECs. These findings suggest that irradiated MOSECs treated with anticancer drugs could be a new immune-therapeutic strategy against advanced ovarian cancers.