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An Uncoupling of Canonical Phenotypic Markers and Functional Potency of Ex Vivo -Expanded Natural Killer Cells
Recent advances in cellular therapies for patients with cancer, including checkpoint blockade and -expanded, tumor-specific T cells, have demonstrated that targeting the immune system is a powerful approach to the elimination of tumor cells. Clinical efforts have also demonstrated limitations, howev...
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Published in: | Frontiers in immunology 2018-02, Vol.9, p.150-150 |
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description | Recent advances in cellular therapies for patients with cancer, including checkpoint blockade and
-expanded, tumor-specific T cells, have demonstrated that targeting the immune system is a powerful approach to the elimination of tumor cells. Clinical efforts have also demonstrated limitations, however, including the potential for tumor cell antigenic drift and neoantigen formation, which promote tumor escape and recurrence, as well as rapid onset of T cell exhaustion
. These findings suggest that antigen unrestricted cells, such as natural killer (NK) cells, may be beneficial for use as an alternative to or in combination with T cell based approaches. Although highly effective in lysing transformed cells, to date, few clinical trials have demonstrated antitumor function or persistence of transferred NK cells. Several recent studies describe methods to expand NK cells for adoptive transfer, although the effects of
expansion are not fully understood. We therefore explored the impact of a clinically validated 12-day expansion protocol using a K562 cell line expressing membrane-bound IL-15 and 4-1BB ligand with high-dose soluble IL-2 on the phenotype and functions of NK cells from healthy donors. Following expansions using this protocol, we found expression of surface proteins that implicate preferential expansion of NK cells that are not fully mature, as is typically associated with highly cytotoxic NK cell subsets. Despite increased expression of markers associated with functional exhaustion in T cells, we found that
-expanded NK cells retained cytokine production capacity and had enhanced tumor cell cytotoxicity. The preferential expansion of an NK cell subset that is phenotypically immature and functionally pleiotropic suggests that adoptively transferred cells may persist better
when compared with previous methods using this approach.
expansion does not quell killer immunoglobulin-like receptor diversity, allowing responsiveness to various factors
that may influence activation and inhibition. Collectively, our data suggest that in addition to robust NK cell expansion that has been described using this method, expanded NK cells may represent an ideal cell therapy that is longer lived, highly potent, and responsive to an array of activating and inhibitory signals. |
doi_str_mv | 10.3389/fimmu.2018.00150 |
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-expanded, tumor-specific T cells, have demonstrated that targeting the immune system is a powerful approach to the elimination of tumor cells. Clinical efforts have also demonstrated limitations, however, including the potential for tumor cell antigenic drift and neoantigen formation, which promote tumor escape and recurrence, as well as rapid onset of T cell exhaustion
. These findings suggest that antigen unrestricted cells, such as natural killer (NK) cells, may be beneficial for use as an alternative to or in combination with T cell based approaches. Although highly effective in lysing transformed cells, to date, few clinical trials have demonstrated antitumor function or persistence of transferred NK cells. Several recent studies describe methods to expand NK cells for adoptive transfer, although the effects of
expansion are not fully understood. We therefore explored the impact of a clinically validated 12-day expansion protocol using a K562 cell line expressing membrane-bound IL-15 and 4-1BB ligand with high-dose soluble IL-2 on the phenotype and functions of NK cells from healthy donors. Following expansions using this protocol, we found expression of surface proteins that implicate preferential expansion of NK cells that are not fully mature, as is typically associated with highly cytotoxic NK cell subsets. Despite increased expression of markers associated with functional exhaustion in T cells, we found that
-expanded NK cells retained cytokine production capacity and had enhanced tumor cell cytotoxicity. The preferential expansion of an NK cell subset that is phenotypically immature and functionally pleiotropic suggests that adoptively transferred cells may persist better
when compared with previous methods using this approach.
expansion does not quell killer immunoglobulin-like receptor diversity, allowing responsiveness to various factors
that may influence activation and inhibition. Collectively, our data suggest that in addition to robust NK cell expansion that has been described using this method, expanded NK cells may represent an ideal cell therapy that is longer lived, highly potent, and responsive to an array of activating and inhibitory signals.</description><identifier>ISSN: 1664-3224</identifier><identifier>EISSN: 1664-3224</identifier><identifier>DOI: 10.3389/fimmu.2018.00150</identifier><identifier>PMID: 29456538</identifier><language>eng</language><publisher>Switzerland: Frontiers Media S.A</publisher><subject>4-1BB Ligand - immunology ; adoptive transfer ; clinical product ; ex vivo expansion ; Humans ; Immunology ; immunotherapy ; Interleukin-15 - immunology ; Interleukin-2 - immunology ; K562 Cells ; Killer Cells, Natural - immunology ; natural killer cells ; Phenotype ; phenotypic analysis</subject><ispartof>Frontiers in immunology, 2018-02, Vol.9, p.150-150</ispartof><rights>Copyright © 2018 Lieberman, DeGolier, Haberthur, Chinn, Moyes, Bouchlaka, Walker, Capitini and Crane. 2018 Lieberman, DeGolier, Haberthur, Chinn, Moyes, Bouchlaka, Walker, Capitini and Crane</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-ed603b58b1475fa597ddedfc008df9e12fb0b324a13ad4ebbe80b9a270f0a123</citedby><cites>FETCH-LOGICAL-c462t-ed603b58b1475fa597ddedfc008df9e12fb0b324a13ad4ebbe80b9a270f0a123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801405/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801405/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29456538$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lieberman, Nicole A P</creatorcontrib><creatorcontrib>DeGolier, Kole</creatorcontrib><creatorcontrib>Haberthur, Kristen</creatorcontrib><creatorcontrib>Chinn, Harrison</creatorcontrib><creatorcontrib>Moyes, Kara W</creatorcontrib><creatorcontrib>Bouchlaka, Myriam N</creatorcontrib><creatorcontrib>Walker, Kirsti L</creatorcontrib><creatorcontrib>Capitini, Christian M</creatorcontrib><creatorcontrib>Crane, Courtney A</creatorcontrib><title>An Uncoupling of Canonical Phenotypic Markers and Functional Potency of Ex Vivo -Expanded Natural Killer Cells</title><title>Frontiers in immunology</title><addtitle>Front Immunol</addtitle><description>Recent advances in cellular therapies for patients with cancer, including checkpoint blockade and
-expanded, tumor-specific T cells, have demonstrated that targeting the immune system is a powerful approach to the elimination of tumor cells. Clinical efforts have also demonstrated limitations, however, including the potential for tumor cell antigenic drift and neoantigen formation, which promote tumor escape and recurrence, as well as rapid onset of T cell exhaustion
. These findings suggest that antigen unrestricted cells, such as natural killer (NK) cells, may be beneficial for use as an alternative to or in combination with T cell based approaches. Although highly effective in lysing transformed cells, to date, few clinical trials have demonstrated antitumor function or persistence of transferred NK cells. Several recent studies describe methods to expand NK cells for adoptive transfer, although the effects of
expansion are not fully understood. We therefore explored the impact of a clinically validated 12-day expansion protocol using a K562 cell line expressing membrane-bound IL-15 and 4-1BB ligand with high-dose soluble IL-2 on the phenotype and functions of NK cells from healthy donors. Following expansions using this protocol, we found expression of surface proteins that implicate preferential expansion of NK cells that are not fully mature, as is typically associated with highly cytotoxic NK cell subsets. Despite increased expression of markers associated with functional exhaustion in T cells, we found that
-expanded NK cells retained cytokine production capacity and had enhanced tumor cell cytotoxicity. The preferential expansion of an NK cell subset that is phenotypically immature and functionally pleiotropic suggests that adoptively transferred cells may persist better
when compared with previous methods using this approach.
expansion does not quell killer immunoglobulin-like receptor diversity, allowing responsiveness to various factors
that may influence activation and inhibition. Collectively, our data suggest that in addition to robust NK cell expansion that has been described using this method, expanded NK cells may represent an ideal cell therapy that is longer lived, highly potent, and responsive to an array of activating and inhibitory signals.</description><subject>4-1BB Ligand - immunology</subject><subject>adoptive transfer</subject><subject>clinical product</subject><subject>ex vivo expansion</subject><subject>Humans</subject><subject>Immunology</subject><subject>immunotherapy</subject><subject>Interleukin-15 - immunology</subject><subject>Interleukin-2 - immunology</subject><subject>K562 Cells</subject><subject>Killer Cells, Natural - immunology</subject><subject>natural killer cells</subject><subject>Phenotype</subject><subject>phenotypic analysis</subject><issn>1664-3224</issn><issn>1664-3224</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNpVkc1vFCEYhydGY5vauyfD0cuuL1-zcDFpNtva2FYP1SsBBrbUGRiZmab738vs1qblAoHf-7zAU1UfMSwpFfKLD103LQlgsQTAHN5Ux7iu2YISwt6-WB9Vp8NwD2UwSSnl76sjIhmvORXHVTyL6Fe0aerbELcoebTWMcVgdYt-3rmYxl0fLLrW-Y_LA9KxQedTtGNIcU6k0UW7m8s2j-h3eEhosXnsS8o16EaPUy6h76FtXUZr17bDh-qd1-3gTp_mk-r2fHO7_ra4-nFxuT67WlhWk3Hhmhqo4cJgtuJec7lqCtFbANF46TDxBgwlTGOqG-aMcQKM1GQFHjQm9KS6PGCbpO9Vn0On804lHdR-I-Wt0nkMtnXKYyGYabgBoMxjLLVkKxBMSl7X1vDC-npg9ZPpXGNdHMurXkFfn8Rwp7bpQXEBmMEM-PwEyOnv5IZRdWGw5Td0dGkaFCliqASB6xKFQ9TmNAzZ-ec2GNQsXe2lq1m62ksvJZ9eXu-54L9i-g8feKn8</recordid><startdate>20180202</startdate><enddate>20180202</enddate><creator>Lieberman, Nicole A P</creator><creator>DeGolier, Kole</creator><creator>Haberthur, Kristen</creator><creator>Chinn, Harrison</creator><creator>Moyes, Kara W</creator><creator>Bouchlaka, Myriam N</creator><creator>Walker, Kirsti L</creator><creator>Capitini, Christian M</creator><creator>Crane, Courtney A</creator><general>Frontiers Media S.A</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><scope>DOA</scope></search><sort><creationdate>20180202</creationdate><title>An Uncoupling of Canonical Phenotypic Markers and Functional Potency of Ex Vivo -Expanded Natural Killer Cells</title><author>Lieberman, Nicole A P ; 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-expanded, tumor-specific T cells, have demonstrated that targeting the immune system is a powerful approach to the elimination of tumor cells. Clinical efforts have also demonstrated limitations, however, including the potential for tumor cell antigenic drift and neoantigen formation, which promote tumor escape and recurrence, as well as rapid onset of T cell exhaustion
. These findings suggest that antigen unrestricted cells, such as natural killer (NK) cells, may be beneficial for use as an alternative to or in combination with T cell based approaches. Although highly effective in lysing transformed cells, to date, few clinical trials have demonstrated antitumor function or persistence of transferred NK cells. Several recent studies describe methods to expand NK cells for adoptive transfer, although the effects of
expansion are not fully understood. We therefore explored the impact of a clinically validated 12-day expansion protocol using a K562 cell line expressing membrane-bound IL-15 and 4-1BB ligand with high-dose soluble IL-2 on the phenotype and functions of NK cells from healthy donors. Following expansions using this protocol, we found expression of surface proteins that implicate preferential expansion of NK cells that are not fully mature, as is typically associated with highly cytotoxic NK cell subsets. Despite increased expression of markers associated with functional exhaustion in T cells, we found that
-expanded NK cells retained cytokine production capacity and had enhanced tumor cell cytotoxicity. The preferential expansion of an NK cell subset that is phenotypically immature and functionally pleiotropic suggests that adoptively transferred cells may persist better
when compared with previous methods using this approach.
expansion does not quell killer immunoglobulin-like receptor diversity, allowing responsiveness to various factors
that may influence activation and inhibition. Collectively, our data suggest that in addition to robust NK cell expansion that has been described using this method, expanded NK cells may represent an ideal cell therapy that is longer lived, highly potent, and responsive to an array of activating and inhibitory signals.</abstract><cop>Switzerland</cop><pub>Frontiers Media S.A</pub><pmid>29456538</pmid><doi>10.3389/fimmu.2018.00150</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 4-1BB Ligand - immunology adoptive transfer clinical product ex vivo expansion Humans Immunology immunotherapy Interleukin-15 - immunology Interleukin-2 - immunology K562 Cells Killer Cells, Natural - immunology natural killer cells Phenotype phenotypic analysis |
title | An Uncoupling of Canonical Phenotypic Markers and Functional Potency of Ex Vivo -Expanded Natural Killer Cells |
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