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Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function
Natural killer (NK) cells are frequently expanded for the clinic using irradiated, engineered K562 feeder cells expressing a core transgene set of membrane-bound (mb) IL15 and/or mbIL21 together with 41BBL. Prior comparisons of mbIL15 to mbIL21 for NK expansion lack comparisons of key attributes of...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618651/ https://www.ncbi.nlm.nih.gov/pubmed/37649085 http://dx.doi.org/10.1158/2326-6066.CIR-23-0151 |
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author | Zhang, Caimei Kadu, Siddhant Xiao, Yansen Johnson, Omar Kelly, Andre O'Connor, Roddy S. Lai, Meizan Kong, Hong Srivatsa, Sriram Tai, Victoria Greenblatt, Eli Holmes, Matthew Riley, James L. June, Carl H. Sheppard, Neil C. |
author_facet | Zhang, Caimei Kadu, Siddhant Xiao, Yansen Johnson, Omar Kelly, Andre O'Connor, Roddy S. Lai, Meizan Kong, Hong Srivatsa, Sriram Tai, Victoria Greenblatt, Eli Holmes, Matthew Riley, James L. June, Carl H. Sheppard, Neil C. |
author_sort | Zhang, Caimei |
collection | PubMed |
description | Natural killer (NK) cells are frequently expanded for the clinic using irradiated, engineered K562 feeder cells expressing a core transgene set of membrane-bound (mb) IL15 and/or mbIL21 together with 41BBL. Prior comparisons of mbIL15 to mbIL21 for NK expansion lack comparisons of key attributes of the resulting NK cells, including their high-dimensional phenotype, polyfunctionality, the breadth and potency of cytotoxicity, cellular metabolism, and activity in xenograft tumor models. Moreover, despite multiple rounds of K562 stimulation, studies of sequential use of mbIL15- and mbIL21-based feeder cells are absent. We addressed these gaps and found that using mbIL15- versus mbIL21-based feeder cells drove distinct phenotypic and functional profiles. Feeder cells expressing mbIL15 alone drove superior functionality by nearly all measures, whereas those expressing mbIL21 alone drove superior yield. In combination, most attributes resembled those imparted by mbIL21, whereas in sequence, NK yield approximated that imparted by the first cytokine, and the phenotype, transcriptome, and function resembled that driven by the second cytokine, highlighting the plasticity of NK cell differentiation. The sequence mbIL21 followed by mbIL15 was advantageous in achieving significant yields of highly functional NK cells that demonstrated equivalent in vivo activity to those expanded by mbIL15 alone in two of three xenograft models. Our findings define the impact of mbIL15 versus mbIL21 during NK expansion and reveal a previously underappreciated tradeoff between NK yield and function for which sequential use of mbIL21-based followed by mbIL15-based feeder cells may be the optimal approach in many settings. |
format | Online Article Text |
id | pubmed-10618651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-106186512023-11-02 Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function Zhang, Caimei Kadu, Siddhant Xiao, Yansen Johnson, Omar Kelly, Andre O'Connor, Roddy S. Lai, Meizan Kong, Hong Srivatsa, Sriram Tai, Victoria Greenblatt, Eli Holmes, Matthew Riley, James L. June, Carl H. Sheppard, Neil C. Cancer Immunol Res Research Articles Natural killer (NK) cells are frequently expanded for the clinic using irradiated, engineered K562 feeder cells expressing a core transgene set of membrane-bound (mb) IL15 and/or mbIL21 together with 41BBL. Prior comparisons of mbIL15 to mbIL21 for NK expansion lack comparisons of key attributes of the resulting NK cells, including their high-dimensional phenotype, polyfunctionality, the breadth and potency of cytotoxicity, cellular metabolism, and activity in xenograft tumor models. Moreover, despite multiple rounds of K562 stimulation, studies of sequential use of mbIL15- and mbIL21-based feeder cells are absent. We addressed these gaps and found that using mbIL15- versus mbIL21-based feeder cells drove distinct phenotypic and functional profiles. Feeder cells expressing mbIL15 alone drove superior functionality by nearly all measures, whereas those expressing mbIL21 alone drove superior yield. In combination, most attributes resembled those imparted by mbIL21, whereas in sequence, NK yield approximated that imparted by the first cytokine, and the phenotype, transcriptome, and function resembled that driven by the second cytokine, highlighting the plasticity of NK cell differentiation. The sequence mbIL21 followed by mbIL15 was advantageous in achieving significant yields of highly functional NK cells that demonstrated equivalent in vivo activity to those expanded by mbIL15 alone in two of three xenograft models. Our findings define the impact of mbIL15 versus mbIL21 during NK expansion and reveal a previously underappreciated tradeoff between NK yield and function for which sequential use of mbIL21-based followed by mbIL15-based feeder cells may be the optimal approach in many settings. American Association for Cancer Research 2023-11-01 2023-08-30 /pmc/articles/PMC10618651/ /pubmed/37649085 http://dx.doi.org/10.1158/2326-6066.CIR-23-0151 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles Zhang, Caimei Kadu, Siddhant Xiao, Yansen Johnson, Omar Kelly, Andre O'Connor, Roddy S. Lai, Meizan Kong, Hong Srivatsa, Sriram Tai, Victoria Greenblatt, Eli Holmes, Matthew Riley, James L. June, Carl H. Sheppard, Neil C. Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function |
title | Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function |
title_full | Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function |
title_fullStr | Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function |
title_full_unstemmed | Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function |
title_short | Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function |
title_sort | sequential exposure to il21 and il15 during human natural killer cell expansion optimizes yield and function |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618651/ https://www.ncbi.nlm.nih.gov/pubmed/37649085 http://dx.doi.org/10.1158/2326-6066.CIR-23-0151 |
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