Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy.
Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy.
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DOI：
10.1158/0008-5472.can-12-2236
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发表时间：
2012-11-01
期刊：
影响因子：
11.2
通讯作者：
Gabrilovich DI
中科院分区：
文献类型：
--
作者：
Ramakrishnan R;Huang C;Cho HI;Lloyd M;Johnson J;Ren X;Altiok S;Sullivan D;Weber J;Celis E;Gabrilovich DI
自噬会减弱常规化疗的疗效，但它对免疫治疗的影响却鲜有研究。在此，我们报告了在体内，化疗使肿瘤细胞更容易被CTL溶解。此外，CTL对不表达抗原的旁观者肿瘤细胞有杀伤作用。这种作用是由肿瘤细胞表面甘露糖-6-磷酸受体(MPR)短暂而戏剧性的上调所介导的。联合治疗的抗肿瘤作用与MPR上调和取消这一事件的动力学有关，从而取消了免疫治疗和化疗的联合作用。在不同的小鼠肿瘤模型和多发性骨髓瘤患者的化疗过程中，观察到肿瘤细胞表面MPR的积聚。值得注意的是，这种效应是化疗诱导的自噬引起受体重新分布的结果。总之，我们的发现揭示了一个分子机制，通过它实现了传统癌症化疗和免疫治疗的抗肿瘤效果。
Autophagy attenuates the efficacy of conventional chemotherapy but its effects on immunotherapy have been little studied. Here, we report that chemotherapy renders tumor cells more susceptible to lysis by CTL in vivo. Moreover, bystander tumor cells that did not express antigen were killed by CTL. This effect was mediated by transient but dramatic upregulation of the mannose-6-phosphate receptor (MPR) on the tumor cell surface. Antitumor effects of combined treatment related to the kinetics of MPR upregulation and abrogation of this event abolished the combined effect of immunotherapy and chemotherapy. MPR accumulation on the tumor cell surface during chemotherapy was observed in different mouse tumor models and in patients with multiple myeloma. Notably, this effect was the result of redistribution of the receptor caused by chemotherapy-inducible autophagy. Together, our findings reveal one molecular mechanism through which the antitumor effects of conventional cancer chemotherapy and immunotherapy are realized.