Disrupting CD47-SIRP alpha axis alone or combined with autophagy depletion for the therapy of glioblastoma
Disrupting CD47-SIRP alpha axis alone or combined with autophagy depletion for the therapy of glioblastoma
复制标题
单独破坏 CD47-SIRP α 轴或联合自噬耗竭治疗胶质母细胞瘤
DOI：
10.1093/carcin/bgy041
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发表时间：
2018
期刊：
影响因子：
4.7
通讯作者：
Ju Dianwen
中科院分区：
文献类型：
--
作者：
Zhang Xuyao;Chen Wei;Fan Jiajun;Wang Shaofei;Xian Zongshu;Luan Jingyun;Li Yubin;Wang Yichen;Nan Yanyang;Luo Man;Li Song;Tian Wenzhi;Ju Dianwen
CD47-targeting immune checkpoint inhibitors have been investigated for immunotherapy of several cancers, glioblastoma, one of the most common tumors in brain, was still a challenge for CD47-targeting therapy. Herein, we reported novel strategies for glioblastoma therapy via blocking CD47-signal regulatory protein-α (SIRPα) by SIRPα-Fc alone or in combination with autophagy inhibition. Our results showed that SIRPα-Fc increased macrophages-triggered cytotoxicity and phagocytosis of glioblastoma cells then elicited potent anti-tumor efficacy. During the treatment, SIRPα-Fc induced autophagy and autophagic flux in glioblastoma cells and Akt/mammalian target of rapamycin (mTOR) inactivation was participated in the autophagy activation. Inhibition of autophagy by pharmacological agents or small-interfering RNA increased SIRPα-Fc-triggered macrophage phagocytosis and cytotoxicity. Importantly, when compared with SIRPα-Fc treatment, blocking both CD47/SIRPα and autophagy significantly increased infiltration of macrophages and apoptosis of tumor cells, triggering potentiated anti-glioblastoma effect and extended median survival. Further experiments showed that adaptive immune response, including CD8+T-cell subsets, was also played a crucial role in SIRPα-Fc-induced glioblastoma rejection. Our results indicated that SIRPα-Fc alone or combined with autophagy inhibitors elicited potent anti-glioblastoma effect, highlighting potential therapeutic strategies of glioblastoma via blocking CD47/SIRPα alone or in combination with autophagy inhibitor.
