Int J Oncol. 2014 May;44(5):1716-26. doi: 10.3892/ijo.2014.2308. Epub 2014 Feb 21.
Paclitaxel-exposed ovarian cancer cells induce cancer‑specific CD4+ T cells after doxorubicin exposure through regulation of MyD88 expression.
Kim JE1, Jang MJ1, Jin DH2, Chung YH1, Choi BS3, Park GB4, Kim YS4, Kim S4, Hur DY4, Hung CF5, Kim D4.
Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
Institute for Innovate Cancer Research, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea.
Department of Preventive Medicine, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
Department of Anatomy, Inje University, College of Medicine, Busan, Republic of Korea.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Ovarian cancer has the highest mortality rate among gynecological malignancies due to high chemoresistance to the combination of platinum with taxane. Immunotherapy against ovarian cancer is a promising strategy to develop from animal-based cancer research. We investigated changes in the immunogenicity of paclitaxel-exposed ovarian cancer cells following exposure to other chemotherapeutic drugs. Murine ovarian surface epithelial cells (MOSECs) showed some resistance to paclitaxel, a first-line therapy for ovarian cancer. However, MOSECs pre-exposed to paclitaxel died through apoptosis after incubation with doxorubicin or cisplatin for 2 h. Injected into mice, the paclitaxel-exposed MOSECs post-treated with doxorubicin induced more MOSEC-specific CD4(+) T cells and extended survival for a greater time than MOSECs treated with paclitaxel alone; and bone marrow-derived dendritic cells (BMDCs) expressed higher levels of co-stimulatory molecules and produced IL-12 after co-culture with paclitaxel-exposed MOSECs treated with doxorubicin. We also observed that in paclitaxel-exposed MOSECs treated with doxorubicin, but not cisplatin, the expression of MyD88 and related target proteins decreased compared to paclitaxel-exposed MOSECs only, while in BMDCs co-cultured with these MOSECs the expression of myeloid differentiation primary response gene 88 (MyD88) increased. These findings suggest that paclitaxel pre-exposed cancer cells treated with doxorubicin can induce significant apoptosis and a therapeutic antitumor immune response in advanced ovarian cancer.