title: Paclitaxel-exposed ovarian cancer cells induce cancer‑specific CD4+ T cells after doxorubicin exposure through regulation of MyD88 expression.
abstract: 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.
authors.affiliation: Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Jee-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Min Ja
authors.initials: MJ
authors.lastname: Jang
authors.affiliation: Institute for Innovate Cancer Research, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.affiliation: Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Department of Preventive Medicine, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Byung-Sun
authors.initials: BS
authors.lastname: Choi
authors.affiliation: Department of Anatomy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Ga Bin
authors.initials: GB
authors.lastname: Park
authors.affiliation: Department of Anatomy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Yeong Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Seonghan
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hur
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.affiliation: Department of Anatomy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015704:CD4 Antigens / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015704:CD4 Antigens; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin