KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape
Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to...
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| Veröffentlicht in: | Nature medicine 2022-10, Vol.28 (10), p.2133-2144 |
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| creator | Li, Ye Basar, Rafet Wang, Guohui Liu, Enli Moyes, Judy S. Li, Li Kerbauy, Lucila N. Uprety, Nadima Fathi, Mohsen Rezvan, Ali Banerjee, Pinaki P. Muniz-Feliciano, Luis Laskowski, Tamara J. Ensley, Emily Daher, May Shanley, Mayra Mendt, Mayela Acharya, Sunil Liu, Bin Biederstädt, Alexander Rafei, Hind Guo, Xingliang Melo Garcia, Luciana Lin, Paul Ang, Sonny Marin, David Chen, Ken Bover, Laura Champlin, Richard E. Varadarajan, Navin Shpall, Elizabeth J. Rezvani, Katayoun |
| description | Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NK
TROG+
) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a ‘don’t kill me’ signal to NK cells upon engagement with their TROG
+
siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
A new dual-chimeric antigen receptor (CAR) system enhances the antitumor activity of CAR natural killer cells and makes them less susceptible to therapeutic resistance in preclinical models. |
| doi_str_mv | 10.1038/s41591-022-02003-x |
| format | Article |
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TROG+
) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a ‘don’t kill me’ signal to NK cells upon engagement with their TROG
+
siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
A new dual-chimeric antigen receptor (CAR) system enhances the antitumor activity of CAR natural killer cells and makes them less susceptible to therapeutic resistance in preclinical models.</description><identifier>ISSN: 1078-8956</identifier><identifier>ISSN: 1546-170X</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-022-02003-x</identifier><identifier>PMID: 36175679</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/250/251 ; 631/67/1059/2325 ; Anticancer properties ; Antigens ; Antigens, Neoplasm ; Antitumor activity ; Autoantigens ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell Line, Tumor ; Chimeric antigen receptors ; Effector cells ; Immunotherapy, Adoptive - methods ; Infectious Diseases ; Killer cell immunoglobulin-like receptors ; Killer Cells, Natural ; Metabolic Diseases ; Molecular Medicine ; Natural killer cells ; Neurosciences ; Plasma membranes ; Receptors ; Receptors, Chimeric Antigen - metabolism ; Self-recognition ; Trogocytosis ; Tumor Escape ; Tumors</subject><ispartof>Nature medicine, 2022-10, Vol.28 (10), p.2133-2144</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2022. corrected publication 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2022. The Author(s), under exclusive licence to Springer Nature America, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-c703931a248b66ae74e04bc2af1bc20d2c85146bae97adc7f2ade8c9dfccb4123</citedby><cites>FETCH-LOGICAL-c474t-c703931a248b66ae74e04bc2af1bc20d2c85146bae97adc7f2ade8c9dfccb4123</cites><orcidid>0000-0001-9971-4166 ; 0000-0002-1197-0198 ; 0000-0003-4013-5279 ; 0000-0002-9599-2246 ; 0000-0001-7727-0875 ; 0000-0003-2805-8231</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41591-022-02003-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41591-022-02003-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36175679$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Ye</creatorcontrib><creatorcontrib>Basar, Rafet</creatorcontrib><creatorcontrib>Wang, Guohui</creatorcontrib><creatorcontrib>Liu, Enli</creatorcontrib><creatorcontrib>Moyes, Judy S.</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Kerbauy, Lucila N.</creatorcontrib><creatorcontrib>Uprety, Nadima</creatorcontrib><creatorcontrib>Fathi, Mohsen</creatorcontrib><creatorcontrib>Rezvan, Ali</creatorcontrib><creatorcontrib>Banerjee, Pinaki P.</creatorcontrib><creatorcontrib>Muniz-Feliciano, Luis</creatorcontrib><creatorcontrib>Laskowski, Tamara J.</creatorcontrib><creatorcontrib>Ensley, Emily</creatorcontrib><creatorcontrib>Daher, May</creatorcontrib><creatorcontrib>Shanley, Mayra</creatorcontrib><creatorcontrib>Mendt, Mayela</creatorcontrib><creatorcontrib>Acharya, Sunil</creatorcontrib><creatorcontrib>Liu, Bin</creatorcontrib><creatorcontrib>Biederstädt, Alexander</creatorcontrib><creatorcontrib>Rafei, Hind</creatorcontrib><creatorcontrib>Guo, Xingliang</creatorcontrib><creatorcontrib>Melo Garcia, Luciana</creatorcontrib><creatorcontrib>Lin, Paul</creatorcontrib><creatorcontrib>Ang, Sonny</creatorcontrib><creatorcontrib>Marin, David</creatorcontrib><creatorcontrib>Chen, Ken</creatorcontrib><creatorcontrib>Bover, Laura</creatorcontrib><creatorcontrib>Champlin, Richard E.</creatorcontrib><creatorcontrib>Varadarajan, Navin</creatorcontrib><creatorcontrib>Shpall, Elizabeth J.</creatorcontrib><creatorcontrib>Rezvani, Katayoun</creatorcontrib><title>KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NK
TROG+
) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a ‘don’t kill me’ signal to NK cells upon engagement with their TROG
+
siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
A new dual-chimeric antigen receptor (CAR) system enhances the antitumor activity of CAR natural killer cells and makes them less susceptible to therapeutic resistance in preclinical models.</description><subject>631/250/251</subject><subject>631/67/1059/2325</subject><subject>Anticancer properties</subject><subject>Antigens</subject><subject>Antigens, Neoplasm</subject><subject>Antitumor activity</subject><subject>Autoantigens</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell Line, Tumor</subject><subject>Chimeric antigen receptors</subject><subject>Effector cells</subject><subject>Immunotherapy, Adoptive - methods</subject><subject>Infectious Diseases</subject><subject>Killer cell immunoglobulin-like receptors</subject><subject>Killer Cells, Natural</subject><subject>Metabolic Diseases</subject><subject>Molecular Medicine</subject><subject>Natural killer cells</subject><subject>Neurosciences</subject><subject>Plasma membranes</subject><subject>Receptors</subject><subject>Receptors, Chimeric Antigen - metabolism</subject><subject>Self-recognition</subject><subject>Trogocytosis</subject><subject>Tumor 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trogocytosis-mediated fratricide and tumor escape</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2022-10-01</date><risdate>2022</risdate><volume>28</volume><issue>10</issue><spage>2133</spage><epage>2144</epage><pages>2133-2144</pages><issn>1078-8956</issn><issn>1546-170X</issn><eissn>1546-170X</eissn><abstract>Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NK
TROG+
) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a ‘don’t kill me’ signal to NK cells upon engagement with their TROG
+
siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
A new dual-chimeric antigen receptor (CAR) system enhances the antitumor activity of CAR natural killer cells and makes them less susceptible to therapeutic resistance in preclinical models.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>36175679</pmid><doi>10.1038/s41591-022-02003-x</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-9971-4166</orcidid><orcidid>https://orcid.org/0000-0002-1197-0198</orcidid><orcidid>https://orcid.org/0000-0003-4013-5279</orcidid><orcidid>https://orcid.org/0000-0002-9599-2246</orcidid><orcidid>https://orcid.org/0000-0001-7727-0875</orcidid><orcidid>https://orcid.org/0000-0003-2805-8231</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2022-10, Vol.28 (10), p.2133-2144 |
| issn | 1078-8956 1546-170X 1546-170X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9942695 |
| source | MEDLINE; SpringerLink Journals; Nature |
| subjects | 631/250/251 631/67/1059/2325 Anticancer properties Antigens Antigens, Neoplasm Antitumor activity Autoantigens Biomedical and Life Sciences Biomedicine Cancer Research Cell Line, Tumor Chimeric antigen receptors Effector cells Immunotherapy, Adoptive - methods Infectious Diseases Killer cell immunoglobulin-like receptors Killer Cells, Natural Metabolic Diseases Molecular Medicine Natural killer cells Neurosciences Plasma membranes Receptors Receptors, Chimeric Antigen - metabolism Self-recognition Trogocytosis Tumor Escape Tumors |
| title | KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T09%3A16%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=KIR-based%20inhibitory%20CARs%20overcome%20CAR-NK%20cell%20trogocytosis-mediated%20fratricide%20and%20tumor%20escape&rft.jtitle=Nature%20medicine&rft.au=Li,%20Ye&rft.date=2022-10-01&rft.volume=28&rft.issue=10&rft.spage=2133&rft.epage=2144&rft.pages=2133-2144&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/s41591-022-02003-x&rft_dat=%3Cproquest_pubme%3E2724089855%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2724089855&rft_id=info:pmid/36175679&rfr_iscdi=true |