Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18
Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18
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DOI：
10.1186/1479-5876-7-104
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发表时间：
2009-12-10
影响因子：
7.4
通讯作者：
Coukos, George
中科院分区：
文献类型：
--
作者：
Alagkiozidis, Ioannis;Facciabene, Andrea;Coukos, George
背景：阿霉素脂质体（Doxil）是一种具有良好血液学毒性的细胞毒性化疗药物。其活性药物阿霉素具有有趣的免疫调节特性。方法：采用ID 8小鼠卵巢癌细胞，通过检测Doxil对卵巢癌细胞MHC Ⅰ类分子和Fas表达的影响，以及对免疫攻击敏感性的影响，研究Doxil对卵巢癌细胞免疫表型的影响。为了评估Doxil与癌症免疫治疗合作的能力，在携带ID 8-VEGF肿瘤的小鼠中体内研究了Doxil与白细胞介素18（IL-18）（一种多效性免疫刺激细胞因子）之间的相互作用。虽然Doxil以剂量依赖性方式杀死ID 8肿瘤细胞，但逃避Doxil诱导的凋亡的肿瘤细胞上调MHC-I和Fas的表面表达，并在体外对CTL杀伤和Fas介导的死亡致敏。因此，我们测试了免疫疗法与Doxil的组合提供积极相互作用的假设。与体内单一疗法相比，IL-18和Doxil的组合显著抑制了肿瘤生长，并且独特地在相当大比例的小鼠中导致完全肿瘤消退和长期抗肿瘤保护。这些数据表明，Doxil有利地改变了逃避直接杀伤的大部分肿瘤的免疫表型，从而创造了通过免疫疗法扩大肿瘤杀伤的机会，其可以通过在体内添加IL-18来资本化。
Background: Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties. Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated.Methods: Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack in vitro. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated in vivo in mice bearing ID8-Vegf tumors.Results: While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death in vitro. We therefore tested the hypothesis that the combination of immunotherapy with Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy in vivo and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice.Conclusion: These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 in vivo.