Cancer Cells Containing Nanoscale Chemotherapeutic Drugs Generate Antiovarian Cancer-specific CD4+ T Cells in Peritoneal Space
Cancer Cells Containing Nanoscale Chemotherapeutic Drugs Generate Antiovarian Cancer-specific CD4+ T Cells in Peritoneal Space
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DOI：
10.1097/cji.0b013e3182328569
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发表时间：
2012-01-01
影响因子：
3.9
通讯作者：
Kim, Daejin
中科院分区：
文献类型：
--
作者：
Kim, Jee-Eun;Jang, Min-Ja;Kim, Daejin
由于卵巢癌患者预后不良，迫切需要开发新的治疗策略。尽管已经研究了几种用于治疗晚期卵巢癌的免疫治疗方法，但它们在临床实践中的实施仍然很低。我们之前的研究表明，阿霉素治疗的小鼠卵巢癌细胞（小鼠卵巢表面上皮细胞（MOSECs））能够在体内将药物传递到邻近细胞以根除肿瘤细胞。在这项研究中，我们假设用抗癌药物治疗的照射肿瘤细胞可能通过细胞间接触和产生抗肿瘤免疫反应杀死其他癌细胞。抗肿瘤药物（多柔比星和顺铂）治疗的MOSECs通过凋亡死亡，且随药物剂量增加而增加。在多柔比星和顺铂共同暴露的MOSECs中，cleaved caspase-3的表达显著增加。抗癌药物治疗的MOSECs产生MOSECs特异性CD4(+) t细胞免疫反应。与多柔比星和顺铂共培养的MOSECs共培养后，骨髓源树突状细胞IL-12p40 mRNA表达上调，IL-6和IL-10 mRNA表达下调。此外，接种多柔比星和顺铂联合治疗MOSECs的小鼠抗肿瘤免疫能力增强，生存期延长。我们还观察到CD4(+) T细胞和自然杀伤细胞对于接种抗癌药物负载MOSECs产生的抗肿瘤免疫至关重要。这些发现表明，用抗癌药物治疗辐照的MOSECs可能是治疗晚期卵巢癌的一种新的免疫治疗策略。
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.