Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer
The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We...
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| Veröffentlicht in: | Science advances 2022-05, Vol.8 (21), p.eabn3774-eabn3774 |
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| creator | Qin, Long Wang, Long Zhang, Junchang Zhou, Huinian Yang, Zhiliang Wang, Yan Cai, Weiwen Wen, Fei Jiang, Xiangyan Zhang, Tiansheng Ye, Huili Long, Bo Qin, Junjie Shi, Wengui Guan, Xiaoying Yu, Zeyuan Yang, Jing Wang, Qi Jiao, Zuoyi |
| description | The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti-Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line-derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor-expressing T cells based on the novel anti-uPAR effectively kill DGC patient-derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner. |
| doi_str_mv | 10.1126/sciadv.abn3774 |
| format | Article |
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Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti-Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line-derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor-expressing T cells based on the novel anti-uPAR effectively kill DGC patient-derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.abn3774</identifier><identifier>PMID: 35613265</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Antineoplastic Agents, Immunological - immunology ; Antineoplastic Agents, Immunological - pharmacology ; Biomedicine and Life Sciences ; Cancer ; Humans ; Mice ; Programmed Cell Death 1 Receptor - antagonists & inhibitors ; Programmed Cell Death 1 Receptor - immunology ; Receptors, Urokinase Plasminogen Activator - antagonists & inhibitors ; Receptors, Urokinase Plasminogen Activator - immunology ; SciAdv r-articles ; Signal Transduction ; Stomach Neoplasms - drug therapy ; Stomach Neoplasms - immunology ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - pathology ; Urokinase-Type Plasminogen Activator - metabolism</subject><ispartof>Science advances, 2022-05, Vol.8 (21), p.eabn3774-eabn3774</ispartof><rights>Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2022 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-b36320c578cb1463e8dd7ce9e29614d47824c7eb7334a9d6358df7d39af7a8053</citedby><cites>FETCH-LOGICAL-c390t-b36320c578cb1463e8dd7ce9e29614d47824c7eb7334a9d6358df7d39af7a8053</cites><orcidid>0000-0001-9995-7176 ; 0000-0001-5414-2141 ; 0000-0003-0727-463X ; 0000-0002-1994-2327 ; 0000-0002-5110-9546 ; 0000-0003-4200-6710 ; 0000-0001-8345-2819 ; 0000-0001-8898-8508 ; 0000-0003-1039-3576 ; 0000-0003-1942-0905</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132454/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132454/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35613265$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Qin, Long</creatorcontrib><creatorcontrib>Wang, Long</creatorcontrib><creatorcontrib>Zhang, Junchang</creatorcontrib><creatorcontrib>Zhou, Huinian</creatorcontrib><creatorcontrib>Yang, Zhiliang</creatorcontrib><creatorcontrib>Wang, Yan</creatorcontrib><creatorcontrib>Cai, Weiwen</creatorcontrib><creatorcontrib>Wen, Fei</creatorcontrib><creatorcontrib>Jiang, Xiangyan</creatorcontrib><creatorcontrib>Zhang, Tiansheng</creatorcontrib><creatorcontrib>Ye, Huili</creatorcontrib><creatorcontrib>Long, Bo</creatorcontrib><creatorcontrib>Qin, Junjie</creatorcontrib><creatorcontrib>Shi, Wengui</creatorcontrib><creatorcontrib>Guan, Xiaoying</creatorcontrib><creatorcontrib>Yu, Zeyuan</creatorcontrib><creatorcontrib>Yang, Jing</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Jiao, Zuoyi</creatorcontrib><title>Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti-Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line-derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor-expressing T cells based on the novel anti-uPAR effectively kill DGC patient-derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner.</description><subject>Animals</subject><subject>Antineoplastic Agents, Immunological - immunology</subject><subject>Antineoplastic Agents, Immunological - pharmacology</subject><subject>Biomedicine and Life Sciences</subject><subject>Cancer</subject><subject>Humans</subject><subject>Mice</subject><subject>Programmed Cell Death 1 Receptor - antagonists & inhibitors</subject><subject>Programmed Cell Death 1 Receptor - immunology</subject><subject>Receptors, Urokinase Plasminogen Activator - antagonists & inhibitors</subject><subject>Receptors, Urokinase Plasminogen Activator - immunology</subject><subject>SciAdv r-articles</subject><subject>Signal Transduction</subject><subject>Stomach Neoplasms - drug therapy</subject><subject>Stomach Neoplasms - immunology</subject><subject>Stomach Neoplasms - metabolism</subject><subject>Stomach Neoplasms - pathology</subject><subject>Urokinase-Type Plasminogen Activator - metabolism</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1r3DAQxUVpaEKaa49Fx1681bfsSyGk6QcEGkJyFmNp7Kjs2q4kB_a_r8JuQ3qagXnzm8c8Qj5wtuFcmM_ZRwhPG-gnaa16Q86EtLoRWrVvX_Wn5CLn34wxrozRvHtHTqU2XAqjz0h__4gJFlxL9DSXBAXHiJkWSCOWOI10vb28o8tccCqxTinU2tx-bTjFYYge_J7GiYY4DGvGpuwXpCNUUuV5mDym9-RkgG3Gi2M9Jw_fru-vfjQ3v77_vLq8abzsWGl6aaRgXtvW99WpxDYE67FD0RmugrKtUN5ib6VU0AUjdRsGG2QHg4WWaXlOvhy4y9rvMPhqOMHWLSnuIO3dDNH9P5nioxvnJ9fVXyitKuDTEZDmPyvm4nYxe9xuYcJ5zU4Yy1i9K0SVbg5Sn-acEw4vZzhzz9m4QzbumE1d-Pja3Iv8XxLyL0ODjhQ</recordid><startdate>20220527</startdate><enddate>20220527</enddate><creator>Qin, Long</creator><creator>Wang, Long</creator><creator>Zhang, Junchang</creator><creator>Zhou, Huinian</creator><creator>Yang, Zhiliang</creator><creator>Wang, Yan</creator><creator>Cai, Weiwen</creator><creator>Wen, Fei</creator><creator>Jiang, Xiangyan</creator><creator>Zhang, Tiansheng</creator><creator>Ye, Huili</creator><creator>Long, Bo</creator><creator>Qin, Junjie</creator><creator>Shi, Wengui</creator><creator>Guan, Xiaoying</creator><creator>Yu, Zeyuan</creator><creator>Yang, Jing</creator><creator>Wang, Qi</creator><creator>Jiao, Zuoyi</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9995-7176</orcidid><orcidid>https://orcid.org/0000-0001-5414-2141</orcidid><orcidid>https://orcid.org/0000-0003-0727-463X</orcidid><orcidid>https://orcid.org/0000-0002-1994-2327</orcidid><orcidid>https://orcid.org/0000-0002-5110-9546</orcidid><orcidid>https://orcid.org/0000-0003-4200-6710</orcidid><orcidid>https://orcid.org/0000-0001-8345-2819</orcidid><orcidid>https://orcid.org/0000-0001-8898-8508</orcidid><orcidid>https://orcid.org/0000-0003-1039-3576</orcidid><orcidid>https://orcid.org/0000-0003-1942-0905</orcidid></search><sort><creationdate>20220527</creationdate><title>Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer</title><author>Qin, Long ; Wang, Long ; Zhang, Junchang ; Zhou, Huinian ; Yang, Zhiliang ; Wang, Yan ; Cai, Weiwen ; Wen, Fei ; Jiang, Xiangyan ; Zhang, Tiansheng ; Ye, Huili ; Long, Bo ; Qin, Junjie ; Shi, Wengui ; Guan, Xiaoying ; Yu, Zeyuan ; Yang, Jing ; Wang, Qi ; Jiao, Zuoyi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-b36320c578cb1463e8dd7ce9e29614d47824c7eb7334a9d6358df7d39af7a8053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Antineoplastic Agents, Immunological - immunology</topic><topic>Antineoplastic Agents, Immunological - pharmacology</topic><topic>Biomedicine and Life Sciences</topic><topic>Cancer</topic><topic>Humans</topic><topic>Mice</topic><topic>Programmed Cell Death 1 Receptor - antagonists & inhibitors</topic><topic>Programmed Cell Death 1 Receptor - immunology</topic><topic>Receptors, Urokinase Plasminogen Activator - antagonists & inhibitors</topic><topic>Receptors, Urokinase Plasminogen Activator - immunology</topic><topic>SciAdv r-articles</topic><topic>Signal Transduction</topic><topic>Stomach Neoplasms - drug therapy</topic><topic>Stomach Neoplasms - immunology</topic><topic>Stomach Neoplasms - metabolism</topic><topic>Stomach Neoplasms - pathology</topic><topic>Urokinase-Type Plasminogen Activator - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Qin, Long</creatorcontrib><creatorcontrib>Wang, Long</creatorcontrib><creatorcontrib>Zhang, Junchang</creatorcontrib><creatorcontrib>Zhou, Huinian</creatorcontrib><creatorcontrib>Yang, Zhiliang</creatorcontrib><creatorcontrib>Wang, Yan</creatorcontrib><creatorcontrib>Cai, Weiwen</creatorcontrib><creatorcontrib>Wen, Fei</creatorcontrib><creatorcontrib>Jiang, Xiangyan</creatorcontrib><creatorcontrib>Zhang, Tiansheng</creatorcontrib><creatorcontrib>Ye, Huili</creatorcontrib><creatorcontrib>Long, Bo</creatorcontrib><creatorcontrib>Qin, Junjie</creatorcontrib><creatorcontrib>Shi, Wengui</creatorcontrib><creatorcontrib>Guan, Xiaoying</creatorcontrib><creatorcontrib>Yu, Zeyuan</creatorcontrib><creatorcontrib>Yang, Jing</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Jiao, Zuoyi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qin, Long</au><au>Wang, Long</au><au>Zhang, Junchang</au><au>Zhou, Huinian</au><au>Yang, Zhiliang</au><au>Wang, Yan</au><au>Cai, Weiwen</au><au>Wen, Fei</au><au>Jiang, Xiangyan</au><au>Zhang, Tiansheng</au><au>Ye, Huili</au><au>Long, Bo</au><au>Qin, Junjie</au><au>Shi, Wengui</au><au>Guan, Xiaoying</au><au>Yu, Zeyuan</au><au>Yang, Jing</au><au>Wang, Qi</au><au>Jiao, Zuoyi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2022-05-27</date><risdate>2022</risdate><volume>8</volume><issue>21</issue><spage>eabn3774</spage><epage>eabn3774</epage><pages>eabn3774-eabn3774</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti-Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line-derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor-expressing T cells based on the novel anti-uPAR effectively kill DGC patient-derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. 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| subjects | Animals Antineoplastic Agents, Immunological - immunology Antineoplastic Agents, Immunological - pharmacology Biomedicine and Life Sciences Cancer Humans Mice Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed Cell Death 1 Receptor - immunology Receptors, Urokinase Plasminogen Activator - antagonists & inhibitors Receptors, Urokinase Plasminogen Activator - immunology SciAdv r-articles Signal Transduction Stomach Neoplasms - drug therapy Stomach Neoplasms - immunology Stomach Neoplasms - metabolism Stomach Neoplasms - pathology Urokinase-Type Plasminogen Activator - metabolism |
| title | Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer |
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