Applied Microbiology and Biotechnology

, Volume 102, Issue 15, pp 6503–6513 | Cite as

Inhibition of autophagy potentiated the anti-tumor effects of VEGF and CD47 bispecific therapy in glioblastoma

  • Xuyao Zhang
  • Shaofei Wang
  • Yanyang Nan
  • Jiajun Fan
  • Wei Chen
  • Jingyun Luan
  • Yichen Wang
  • Yanxu Liang
  • Song Li
  • Wenzhi Tian
  • Dianwen JuEmail author
Biotechnologically relevant enzymes and proteins


Glioblastoma, characterized by extensive microvascular proliferation and invasive tumor growth, is one of the most common and lethal malignancies in adults. Benefits of the conventional anti-angiogenic therapy were only observed in a subset of patients and limited by diverse relapse mechanism. Fortunately, recent advances in cancer immunotherapy have offered new hope for patients with glioblastoma. Herein, we reported a novel dual-targeting therapy for glioblastoma through simultaneous blockade of VEGF and CD47 signaling. Our results showed that VEGFR1D2-SIRPαD1, a VEGF and CD47 bispecific fusion protein, exerted potent anti-tumor effects via suppressing VEGF-induced angiogenesis and activating macrophage-mediated phagocytosis. Meanwhile, autophagy was activated by VEGFR1D2-SIRPαD1 through inactivating Akt/mTOR and Erk pathways in glioblastoma cells. Importantly, autophagy inhibitor or knockdown of autophagy-related protein 5 potentiated VEGFR1D2-SIRPαD1-induced macrophage phagocytosis and cytotoxicity against glioblastoma cells. Moreover, suppression of autophagy led to increased macrophage infiltration, angiogenesis inhibition, and tumor cell apoptosis triggered by VEGF and CD47 dual-targeting therapy, thus eliciting enhanced anti-tumor effects in glioblastoma. Our data revealed that VEGFR1D2-SIRPαD1 alone or in combination with autophagy inhibitor could effectively elicit potent anti-tumor effects, highlighting potential therapeutic strategies for glioblastoma through disrupting angiogenetic axis and CD47-SIRPα anti-phagocytic axis alone or in combination with autophagy inhibition.


Anti-angiogenesis Macrophage phagocytosis Bispecific therapy Autophagy Combination therapy 



The work was funded by the National Key Basic Research Program of China (grant number 2015CB931800), the National Natural Science Foundation of China (grant number 81573332 and 81773620), and the Special Research Foundation of State Key Laboratory of Medical Genomics and Collaborative Innovation Center of Systems Biomedicine.

Compliance with ethical standards

Conflict of interest

Wenzhi Tian is the founder and Song Li is the employee of ImmuneOnco Biopharma (Shanghai) Co., Ltd. Others declared no conflict of interest.

Ethical approval

All experimental procedures involving animals were conducted in accordance with the standards approved by Animal Ethical Committee of School of Pharmacy at Fudan University.

Supplementary material

253_2018_9069_MOESM1_ESM.pdf (1.5 mb)
ESM 1 (PDF 1507 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Minhang Branch, Zhongshan Hospital, Fudan University/Institute of Fudan-Minhang Academic Health System, Minhang HospitalFudan UniversityShanghaiChina
  2. 2.Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of PharmacyFudan UniversityShanghaiChina
  3. 3.ImmuneOnco Biopharma (Shanghai) Co., Ltd.ShanghaiChina

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