Modeling the response to interleukin-21 to inform natural killer cell immunotherapy
Modeling the response to interleukin-21 to inform natural killer cell immunotherapy
Natural killer (NK) cells are emerging agents for cancer therapy. Several different cytokines are used to generate NK cells for adoptive immunotherapy including interleukin (IL)-2, IL-12, IL-15 and IL-18 in solution, and membrane-bound IL-21. These cytokines drive NK cell activation through the integration of signal transducers and activators of transcription (STAT) and nuclear factor-kappa B (NF-κB) pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations for both proliferation and cytotoxicity. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with mathematical modeling using feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy of activated STATs and NF-κB transcription factors between priming and post-priming phases. The use of IL-21 in solution in the priming of NK cell culture resulted in an improved NK cell proliferation, without compromising cytotoxicity potential or interferon gamma secretion against hepatocellular carcinoma cell lines. Our work provides an integrative framework for interrogating NK cell proliferation and activation for cancer immunotherapy.
Carcinoma, Hepatocellular/immunology, Cell Line, Tumor, Cell Proliferation/drug effects, Cytotoxicity, Immunologic/drug effects, Humans, Immunotherapy, Adoptive/methods, Immunotherapy/methods, Interferon-gamma/metabolism, Interleukin-21, Interleukins/pharmacology, Killer Cells, Natural/immunology, Liver Neoplasms/immunology, Lymphocyte Activation/drug effects, NF-kappa B/metabolism, NK cells, predictive model, proliferation, linear regression, STAT, cytokines
192-212
Nayak, Indrani
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Biondo, Rosalba
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Stewart, William C.
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Fulton, Rebecca J.
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Möker, Nina
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Zhang, Congcong
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Khakoo, Salim I.
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Das, Jayajit
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4 February 2025
Nayak, Indrani
efe3f409-b980-45a4-97e4-e0d213e3dbb6
Biondo, Rosalba
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Stewart, William C.
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Fulton, Rebecca J.
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Möker, Nina
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Zhang, Congcong
c0d28b06-2ec6-4dc5-a0d6-09f4591446cc
Khakoo, Salim I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273
Das, Jayajit
989b840f-3503-41a1-aacb-65448949f07d
Nayak, Indrani, Biondo, Rosalba, Stewart, William C., Fulton, Rebecca J., Möker, Nina, Zhang, Congcong, Khakoo, Salim I. and Das, Jayajit
(2025)
Modeling the response to interleukin-21 to inform natural killer cell immunotherapy.
Immunology and Cell Biology, 103 (2), .
(doi:10.1111/imcb.12848).
Abstract
Natural killer (NK) cells are emerging agents for cancer therapy. Several different cytokines are used to generate NK cells for adoptive immunotherapy including interleukin (IL)-2, IL-12, IL-15 and IL-18 in solution, and membrane-bound IL-21. These cytokines drive NK cell activation through the integration of signal transducers and activators of transcription (STAT) and nuclear factor-kappa B (NF-κB) pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations for both proliferation and cytotoxicity. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with mathematical modeling using feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy of activated STATs and NF-κB transcription factors between priming and post-priming phases. The use of IL-21 in solution in the priming of NK cell culture resulted in an improved NK cell proliferation, without compromising cytotoxicity potential or interferon gamma secretion against hepatocellular carcinoma cell lines. Our work provides an integrative framework for interrogating NK cell proliferation and activation for cancer immunotherapy.
Text
Immunology Cell Biology - 2025 - Nayak - Modeling the response to interleukin‐21 to inform natural killer cell
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More information
Accepted/In Press date: 15 December 2024
e-pub ahead of print date: 25 January 2025
Published date: 4 February 2025
Keywords:
Carcinoma, Hepatocellular/immunology, Cell Line, Tumor, Cell Proliferation/drug effects, Cytotoxicity, Immunologic/drug effects, Humans, Immunotherapy, Adoptive/methods, Immunotherapy/methods, Interferon-gamma/metabolism, Interleukin-21, Interleukins/pharmacology, Killer Cells, Natural/immunology, Liver Neoplasms/immunology, Lymphocyte Activation/drug effects, NF-kappa B/metabolism, NK cells, predictive model, proliferation, linear regression, STAT, cytokines
Identifiers
Local EPrints ID: 502155
URI: http://eprints.soton.ac.uk/id/eprint/502155
ISSN: 0818-9641
PURE UUID: d9815991-7afb-42cf-badc-a701c4455b5b
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Date deposited: 17 Jun 2025 16:50
Last modified: 22 Aug 2025 01:49
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Contributors
Author:
Indrani Nayak
Author:
Rosalba Biondo
Author:
William C. Stewart
Author:
Rebecca J. Fulton
Author:
Nina Möker
Author:
Congcong Zhang
Author:
Jayajit Das
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