Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD

Mayra Shanley; May Daher; Jinzhuang Dou; Sufang Li; Rafet Basar; Hind Rafei; Merve Dede; Joy Gumin; Jezreel Pantaleόn Garcίa; Ana Karen Nunez Cortes; Shan He; Corry M. Jones; Sunil Acharya; Natalie W. Fowlkes; Donghai Xiong; Sanjay Singh; Hila Shaim; Samantha Claire Hicks; Bin Liu; Abhinav Jain; Mohammad Fayyad Zaman; Qi Miao; Ye Li; Nadima Uprety; Enli Liu; Luis Muniz-Feliciano; Gary M. Deyter; Vakul Mohanty; Patrick Zhang; Scott E. Evans; Elizabeth J. Shpall; Frederick F. Lang; Ken Chen; Katayoun Rezvani

doi:10.1016/j.ccell.2024.07.007

Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD

Mayra Shanley, May Daher, Jinzhuang Dou, Sufang Li, Rafet Basar, Hind Rafei, Merve Dede, Joy Gumin, Jezreel Pantaleόn Garcίa, Ana Karen Nunez Cortes, Shan He, Corry M. Jones, Sunil Acharya, Natalie W. Fowlkes, Donghai Xiong, Sanjay Singh, Hila Shaim, Samantha Claire Hicks, Bin Liu, Abhinav JainMohammad Fayyad Zaman, Qi Miao, Ye Li, Nadima Uprety, Enli Liu, Luis Muniz-Feliciano, Gary M. Deyter, Vakul Mohanty, Patrick Zhang, Scott E. Evans, Elizabeth J. Shpall, Frederick F. Lang, Ken Chen, Katayoun Rezvani

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.

Original language	English (US)
Pages (from-to)	1450-1466.e11
Journal	Cancer cell
Volume	42
Issue number	8
DOIs	https://doi.org/10.1016/j.ccell.2024.07.007
State	Published - Aug 12 2024

Keywords

CEBPD
GBM
IL-21
NK cells

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2024.07.007

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Shanley, M., Daher, M., Dou, J., Li, S., Basar, R., Rafei, H., Dede, M., Gumin, J., Pantaleόn Garcίa, J., Nunez Cortes, A. K., He, S., Jones, C. M., Acharya, S., Fowlkes, N. W., Xiong, D., Singh, S., Shaim, H., Hicks, S. C., Liu, B., ... Rezvani, K. (2024). Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD. Cancer cell, 42(8), 1450-1466.e11. https://doi.org/10.1016/j.ccell.2024.07.007

Shanley, M , Daher, M , Dou, J, Li, S, Basar, R , Rafei, H, Dede, M, Gumin, J, Pantaleόn Garcίa, J, Nunez Cortes, AK, He, S, Jones, CM , Acharya, S , Fowlkes, NW , Xiong, D , Singh, S, Shaim, H, Hicks, SC, Liu, B , Jain, A, Zaman, MF, Miao, Q, Li, Y, Uprety, N, Liu, E, Muniz-Feliciano, L, Deyter, GM, Mohanty, V, Zhang, P, Evans, SE , Shpall, EJ , Lang, FF , Chen, K & Rezvani, K 2024, 'Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD', Cancer cell, vol. 42, no. 8, pp. 1450-1466.e11. https://doi.org/10.1016/j.ccell.2024.07.007

@article{64134554a28b4b00a1ecbb147fe0de9b,

title = "Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD",

abstract = "Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.",

keywords = "CEBPD, GBM, IL-21, NK cells",

author = "Mayra Shanley and May Daher and Jinzhuang Dou and Sufang Li and Rafet Basar and Hind Rafei and Merve Dede and Joy Gumin and {Pantaleόn Garcίa}, Jezreel and {Nunez Cortes}, {Ana Karen} and Shan He and Jones, {Corry M.} and Sunil Acharya and Fowlkes, {Natalie W.} and Donghai Xiong and Sanjay Singh and Hila Shaim and Hicks, {Samantha Claire} and Bin Liu and Abhinav Jain and Zaman, {Mohammad Fayyad} and Qi Miao and Ye Li and Nadima Uprety and Enli Liu and Luis Muniz-Feliciano and Deyter, {Gary M.} and Vakul Mohanty and Patrick Zhang and Evans, {Scott E.} and Shpall, {Elizabeth J.} and Lang, {Frederick F.} and Ken Chen and Katayoun Rezvani",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = aug,

day = "12",

doi = "10.1016/j.ccell.2024.07.007",

language = "English (US)",

volume = "42",

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T1 - Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD

AU - Shanley, Mayra

AU - Daher, May

AU - Dou, Jinzhuang

AU - Li, Sufang

AU - Basar, Rafet

AU - Rafei, Hind

AU - Dede, Merve

AU - Gumin, Joy

AU - Pantaleόn Garcίa, Jezreel

AU - Nunez Cortes, Ana Karen

AU - He, Shan

AU - Jones, Corry M.

AU - Acharya, Sunil

AU - Fowlkes, Natalie W.

AU - Xiong, Donghai

AU - Singh, Sanjay

AU - Shaim, Hila

AU - Hicks, Samantha Claire

AU - Liu, Bin

AU - Jain, Abhinav

AU - Zaman, Mohammad Fayyad

AU - Miao, Qi

AU - Li, Ye

AU - Uprety, Nadima

AU - Liu, Enli

AU - Muniz-Feliciano, Luis

AU - Deyter, Gary M.

AU - Mohanty, Vakul

AU - Zhang, Patrick

AU - Evans, Scott E.

AU - Shpall, Elizabeth J.

AU - Lang, Frederick F.

AU - Chen, Ken

AU - Rezvani, Katayoun

PY - 2024/8/12

Y1 - 2024/8/12

N2 - Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.

AB - Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.

KW - CEBPD

KW - GBM

KW - IL-21

KW - NK cells

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DO - 10.1016/j.ccell.2024.07.007

M3 - Article

C2 - 39137729

AN - SCOPUS:85200539710

SN - 1535-6108

VL - 42

SP - 1450-1466.e11

JO - Cancer cell

JF - Cancer cell

IS - 8

ER -

Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD

Abstract

Keywords

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