Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non-Small Cell Lung Cancer.
Identifieur interne : 000C93 ( Main/Exploration ); précédent : 000C92; suivant : 000C94Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non-Small Cell Lung Cancer.
Auteurs : Xuyao Zhang [République populaire de Chine] ; Jiajun Fan [République populaire de Chine] ; Shaofei Wang [République populaire de Chine] ; Yubin Li [République populaire de Chine] ; Yichen Wang [République populaire de Chine] ; Song Li [République populaire de Chine] ; Jingyun Luan [République populaire de Chine] ; Ziyu Wang [République populaire de Chine] ; Ping Song [République populaire de Chine] ; Qicheng Chen [République populaire de Chine] ; Wenzhi Tian [République populaire de Chine] ; Dianwen Ju [République populaire de Chine]Source :
- Cancer immunology research [ 2326-6074 ] ; 2017.
Descripteurs français
- KwdFr :
- Animaux, Association de médicaments, Autophagie (), Carcinome pulmonaire non à petites cellules (immunologie), Carcinome pulmonaire non à petites cellules (traitement médicamenteux), Chloroquine (pharmacologie), Chloroquine (usage thérapeutique), Espèces réactives de l'oxygène (métabolisme), Femelle, Humains, Lignée cellulaire, Lignée cellulaire tumorale, Phagocytose (), Protéines de fusion recombinantes (pharmacologie), Protéines de fusion recombinantes (usage thérapeutique), Protéines proto-oncogènes c-akt (métabolisme), Souris, Souris de lignée BALB C, Souris nude, Survie cellulaire (), Sérine-thréonine kinases TOR (métabolisme), Tumeurs du poumon (immunologie), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- immunologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- métabolisme : Espèces réactives de l'oxygène, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- pharmacologie : Chloroquine, Protéines de fusion recombinantes.
- traitement médicamenteux : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- usage thérapeutique : Chloroquine, Protéines de fusion recombinantes.
- Animaux, Association de médicaments, Autophagie, Femelle, Humains, Lignée cellulaire, Lignée cellulaire tumorale, Phagocytose, Souris, Souris de lignée BALB C, Souris nude, Survie cellulaire.
English descriptors
- KwdEn :
- Animals, Antineoplastic Agents, Immunological (pharmacology), Antineoplastic Agents, Immunological (therapeutic use), Autophagy (drug effects), CD47 Antigen (antagonists & inhibitors), CD47 Antigen (immunology), Carcinoma, Non-Small-Cell Lung (drug therapy), Carcinoma, Non-Small-Cell Lung (immunology), Cell Line, Cell Line, Tumor, Cell Survival (drug effects), Chloroquine (pharmacology), Chloroquine (therapeutic use), Drug Therapy, Combination, Female, Humans, Lung Neoplasms (drug therapy), Lung Neoplasms (immunology), Mice, Mice, Inbred BALB C, Mice, Nude, Phagocytosis (drug effects), Proto-Oncogene Proteins c-akt (metabolism), Reactive Oxygen Species (metabolism), Recombinant Fusion Proteins (pharmacology), Recombinant Fusion Proteins (therapeutic use), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , antagonists & inhibitors : CD47 Antigen.
- chemical , immunology : CD47 Antigen.
- chemical , metabolism : Proto-Oncogene Proteins c-akt, Reactive Oxygen Species, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antineoplastic Agents, Immunological, Chloroquine, Recombinant Fusion Proteins.
- chemical , therapeutic use : Antineoplastic Agents, Immunological, Chloroquine, Recombinant Fusion Proteins.
- drug effects : Autophagy, Cell Survival, Phagocytosis.
- drug therapy : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- immunology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- Animals, Cell Line, Cell Line, Tumor, Drug Therapy, Combination, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Nude.
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.
DOI: 10.1158/2326-6066.CIR-16-0398
PubMed: 28351890
Affiliations:
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Le document en format XML
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China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Tian, Wenzhi" sort="Tian, Wenzhi" uniqKey="Tian W" first="Wenzhi" last="Tian">Wenzhi Tian</name><affiliation wicri:level="1"><nlm:affiliation>ImmuneOnco Biopharma (Shanghai) Co., Ltd., Shanghai, P. R. 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R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Fan, Jiajun" sort="Fan, Jiajun" uniqKey="Fan J" first="Jiajun" last="Fan">Jiajun Fan</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Shaofei" sort="Wang, Shaofei" uniqKey="Wang S" first="Shaofei" last="Wang">Shaofei Wang</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Li, Yubin" sort="Li, Yubin" uniqKey="Li Y" first="Yubin" last="Li">Yubin Li</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Yichen" sort="Wang, Yichen" uniqKey="Wang Y" first="Yichen" last="Wang">Yichen Wang</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Li, Song" sort="Li, Song" uniqKey="Li S" first="Song" last="Li">Song Li</name><affiliation wicri:level="1"><nlm:affiliation>ImmuneOnco Biopharma (Shanghai) Co., Ltd., Shanghai, P. R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>ImmuneOnco Biopharma (Shanghai) Co., Ltd., Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Luan, Jingyun" sort="Luan, Jingyun" uniqKey="Luan J" first="Jingyun" last="Luan">Jingyun Luan</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Ziyu" sort="Wang, Ziyu" uniqKey="Wang Z" first="Ziyu" last="Wang">Ziyu Wang</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Song, Ping" sort="Song, Ping" uniqKey="Song P" first="Ping" last="Song">Ping Song</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Qicheng" sort="Chen, Qicheng" uniqKey="Chen Q" first="Qicheng" last="Chen">Qicheng Chen</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy and The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Tian, Wenzhi" sort="Tian, Wenzhi" uniqKey="Tian W" first="Wenzhi" last="Tian">Wenzhi Tian</name><affiliation wicri:level="1"><nlm:affiliation>ImmuneOnco Biopharma (Shanghai) Co., Ltd., Shanghai, P. R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>ImmuneOnco Biopharma (Shanghai) Co., Ltd., Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Ju, Dianwen" sort="Ju, Dianwen" uniqKey="Ju D" first="Dianwen" last="Ju">Dianwen Ju</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country wicri:rule="url">République populaire de Chine</country></affiliation></author></analytic><series><title level="j">Cancer immunology research</title><idno type="eISSN">2326-6074</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antineoplastic Agents, Immunological (pharmacology)</term><term>Antineoplastic Agents, Immunological (therapeutic use)</term><term>Autophagy (drug effects)</term><term>CD47 Antigen (antagonists & inhibitors)</term><term>CD47 Antigen (immunology)</term><term>Carcinoma, Non-Small-Cell Lung (drug therapy)</term><term>Carcinoma, Non-Small-Cell Lung (immunology)</term><term>Cell Line</term><term>Cell Line, Tumor</term><term>Cell Survival (drug effects)</term><term>Chloroquine (pharmacology)</term><term>Chloroquine (therapeutic use)</term><term>Drug Therapy, Combination</term><term>Female</term><term>Humans</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (immunology)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Nude</term><term>Phagocytosis (drug effects)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Reactive Oxygen Species (metabolism)</term><term>Recombinant Fusion Proteins (pharmacology)</term><term>Recombinant Fusion Proteins (therapeutic use)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Association de médicaments</term><term>Autophagie ()</term><term>Carcinome pulmonaire non à petites cellules (immunologie)</term><term>Carcinome pulmonaire non à petites cellules (traitement médicamenteux)</term><term>Chloroquine (pharmacologie)</term><term>Chloroquine (usage thérapeutique)</term><term>Espèces réactives de l'oxygène (métabolisme)</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire</term><term>Lignée cellulaire tumorale</term><term>Phagocytose ()</term><term>Protéines de fusion recombinantes (pharmacologie)</term><term>Protéines de fusion recombinantes (usage thérapeutique)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris nude</term><term>Survie cellulaire ()</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Tumeurs du poumon (immunologie)</term><term>Tumeurs du poumon (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>CD47 Antigen</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>CD47 Antigen</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Proto-Oncogene Proteins c-akt</term><term>Reactive Oxygen Species</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents, Immunological</term><term>Chloroquine</term><term>Recombinant Fusion Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antineoplastic Agents, Immunological</term><term>Chloroquine</term><term>Recombinant Fusion Proteins</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>Cell Survival</term><term>Phagocytosis</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Espèces réactives de l'oxygène</term><term>Protéines proto-oncogènes c-akt</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Chloroquine</term><term>Protéines de fusion recombinantes</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Chloroquine</term><term>Protéines de fusion recombinantes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Cell Line, Tumor</term><term>Drug Therapy, Combination</term><term>Female</term><term>Humans</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Nude</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Association de médicaments</term><term>Autophagie</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire</term><term>Lignée cellulaire tumorale</term><term>Phagocytose</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris nude</term><term>Survie cellulaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. <i>Cancer Immunol Res; 5(5); 363-75. ©2017 AACR</i><i>See related Spotlight by Kaufman, p. 355.</i></div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Zhang, Xuyao" sort="Zhang, Xuyao" uniqKey="Zhang X" first="Xuyao" last="Zhang">Xuyao Zhang</name></noRegion><name sortKey="Chen, Qicheng" sort="Chen, Qicheng" uniqKey="Chen Q" first="Qicheng" last="Chen">Qicheng Chen</name><name sortKey="Fan, Jiajun" sort="Fan, Jiajun" uniqKey="Fan J" first="Jiajun" last="Fan">Jiajun Fan</name><name sortKey="Ju, Dianwen" sort="Ju, Dianwen" uniqKey="Ju D" first="Dianwen" last="Ju">Dianwen Ju</name><name sortKey="Li, Song" sort="Li, Song" uniqKey="Li S" first="Song" last="Li">Song Li</name><name sortKey="Li, Yubin" sort="Li, Yubin" uniqKey="Li Y" first="Yubin" last="Li">Yubin Li</name><name sortKey="Luan, Jingyun" sort="Luan, Jingyun" uniqKey="Luan J" first="Jingyun" last="Luan">Jingyun Luan</name><name sortKey="Song, Ping" sort="Song, Ping" uniqKey="Song P" first="Ping" last="Song">Ping Song</name><name sortKey="Tian, Wenzhi" sort="Tian, Wenzhi" uniqKey="Tian W" first="Wenzhi" last="Tian">Wenzhi Tian</name><name sortKey="Wang, Shaofei" sort="Wang, Shaofei" uniqKey="Wang S" first="Shaofei" last="Wang">Shaofei Wang</name><name sortKey="Wang, Yichen" sort="Wang, Yichen" uniqKey="Wang Y" first="Yichen" last="Wang">Yichen Wang</name><name sortKey="Wang, Ziyu" sort="Wang, Ziyu" uniqKey="Wang Z" first="Ziyu" last="Wang">Ziyu Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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