Cyclophosphamide Synergizes with Type I Interferons through Systemic Dendritic Cell Reactivation and Induction of Immunogenic Tumor Apoptosis
Cyclophosphamide Synergizes with Type I Interferons through Systemic Dendritic Cell Reactivation and Induction of Immunogenic Tumor Apoptosis
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DOI：
10.1158/0008-5472.can-10-2788
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Bracci, Laura
中科院分区：
文献类型：
--
作者：
Schiavoni, Giovanna;Sistigu, Antonella;Bracci, Laura
成功的化疗是肿瘤相关因素和宿主免疫应答共同作用的结果。令人信服的证据表明，一些化疗药物可以诱导免疫原性类型的细胞死亡，刺激肿瘤特异性免疫。在此，我们表明环磷酰胺（CTX）在体内发挥两种与诱导抗肿瘤免疫相关的作用：（i）通过内源性I型干扰素（IFN-I）介导的对树突状细胞（DC）稳态的影响，导致CD 8 α（+）DC的优先扩增，该DC是参与细胞衍生抗原交叉呈递的主要亚群;和（ii）诱导肿瘤细胞死亡，具有明确的免疫原性特征，能够刺激肿瘤浸润、肿瘤凋亡物质的吞噬和CD 8 α（+）DC的CD 8 T细胞交叉致敏。值得注意的是，CTX的抗肿瘤作用被IFN-I有效地放大，前者提供抗原来源和DC隔室的“重置”，后者为T细胞交叉引发提供最佳共刺激，导致诱导强烈的抗肿瘤应答和肿瘤排斥。这些结果为开发针对癌症患者的更有效的化学免疫疗法提供了新的视角。Cancer Res; 71（3）; 768-78.（C）2010年AACR。
Successful chemotherapy accounts for both tumor-related factors and host immune response. Compelling evidence suggests that some chemotherapeutic agents can induce an immunogenic type of cell death stimulating tumor-specific immunity. Here, we show that cyclophosphamide (CTX) exerts two types of actions relevant for the induction of antitumor immunity in vivo: (i) effect on dendritic cell (DC) homeostasis, mediated by endogenous type I interferons (IFN-I), leading to the preferential expansion of CD8 alpha(+) DC, the main subset involved in the cross-presentation of cell-derived antigens; and (ii) induction of tumor cell death with clear-cut immunogenic features capable of stimulating tumor infiltration, engulfment of tumor apoptotic material, and CD8 T-cell cross-priming by CD8 alpha(+) DC. Notably, the antitumor effects of CTX were efficiently amplified by IFN-I, the former providing a source of antigen and a "resetting" of the DC compartment and the latter supplying optimal costimulation for T-cell cross-priming, resulting in the induction of a strong antitumor response and tumor rejection. These results disclose new perspectives for the development of targeted and more effective chemoimmunotherapy treatments of cancer patients. Cancer Res; 71(3); 768-78. (C)2010 AACR.