title: Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non-Small Cell Lung Cancer.
abstract: CD47-specific antibodies and fusion proteins that block CD47-SIRPα signaling are employed as antitumor agents for several cancers. Here, we investigated the synergistic antitumor effect of simultaneously targeting CD47 and autophagy in non-small cell lung cancer (NSCLC). SIRPαD1-Fc, a novel CD47-targeting fusion protein, was generated and was found to increase the phagocytic and cytotoxic activities of macrophages against NSCLC cells. During this process, autophagy was markedly triggered, which was characterized by the three main stages of autophagic flux, including formation and accumulation of autophagosomes, fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Meanwhile, reactive oxygen species and inactivation of mTOR were shown to be involved in autophagy initiation in SIRPαD1-Fc-treated cells, indicating a probable mechanism for autophagy activation after targeting CD47 by SIRPαD1-Fc. Inhibition of autophagy enhanced macrophage-mediated phagocytosis and cytotoxicity against SIRPαD1-Fc-treated NSCLC cells. In addition, simultaneously targeting both CD47 and autophagy in NSCLC xenograft models elicited enhanced antitumor effects, with recruitment of macrophages, activated caspase-3, and overproduction of ROS at the tumor site. Our data elucidated the cytoprotective role of autophagy in CD47-targeted therapy and highlighted the potential approach for NSCLC treatment by simultaneously targeting CD47 and autophagy.Cancer Immunol Res; 5(5); 363-75. ©2017 AACRSee related Spotlight by Kaufman, p. 355.
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.
authors.forename: Xuyao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.
authors.forename: Shaofei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: ImmuneOnco Biopharma (Shanghai) Co., Ltd., Shanghai, P. R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Luan
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China.
authors.forename: Qicheng
authors.initials: Q
authors.lastname: Chen
authors.affiliation: ImmuneOnco Biopharma (Shanghai) Co., Ltd., Shanghai, P. R. China.
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Tian
authors.affiliation: Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, P. R. China. dianwenju@fudan.edu.cn.
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D051928:CD47 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010587:Phagocytosis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000074322:Antineoplastic Agents, Immunological; D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D002738:Chloroquine; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases