An NK-like CAR T cell transition in CAR T cell dysfunction

Charly R. Good; M. Angela Aznar; Shunichiro Kuramitsu; Parisa Samareh; Sangya Agarwal; Greg Donahue; Kenichi Ishiyama; Nils Wellhausen; Austin K. Rennels; Yujie Ma; Lifeng Tian; Sonia Guedan; Katherine A. Alexander; Zhen Zhang; Philipp C. Rommel; Nathan Singh; Karl M. Glastad; Max W. Richardson; Keisuke Watanabe; Janos L. Tanyi; Mark H. O'Hara; Marco Ruella; Simon F. Lacey; Edmund K. Moon; Stephen J. Schuster; Steven M. Albelda; Lewis L. Lanier; Regina M. Young; Shelley L. Berger; Carl H. June

doi:10.1016/j.cell.2021.11.016

An NK-like CAR T cell transition in CAR T cell dysfunction

Charly R. Good, M. Angela Aznar, Shunichiro Kuramitsu, Parisa Samareh, Sangya Agarwal, Greg Donahue, Kenichi Ishiyama, Nils Wellhausen, Austin K. Rennels, Yujie Ma, Lifeng Tian, Sonia Guedan, Katherine A. Alexander, Zhen Zhang, Philipp C. Rommel, Nathan Singh, Karl M. Glastad, Max W. Richardson, Keisuke Watanabe, Janos L. TanyiMark H. O'Hara, Marco Ruella, Simon F. Lacey, Edmund K. Moon, Stephen J. Schuster, Steven M. Albelda, Lewis L. Lanier, Regina M. Young, Shelley L. Berger, Carl H. June

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

228 Scopus citations

Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.

Original language	English
Pages (from-to)	6081-6100.e26
Journal	Cell
Volume	184
Issue number	25
DOIs	https://doi.org/10.1016/j.cell.2021.11.016
State	Published - Dec 9 2021

Keywords

CAR T cell
ID3
NK-like T cell
SOX4
T cell dysfunction
T cell exhaustion
cancer
cell transfer therapy
immunology
immunotherapy
pancreatic cancer
single-cell RNA-seq

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10.1016/j.cell.2021.11.016

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Good, C. R., Aznar, M. A., Kuramitsu, S., Samareh, P., Agarwal, S., Donahue, G., Ishiyama, K., Wellhausen, N., Rennels, A. K., Ma, Y., Tian, L., Guedan, S., Alexander, K. A., Zhang, Z., Rommel, P. C., Singh, N., Glastad, K. M., Richardson, M. W., Watanabe, K., ... June, C. H. (2021). An NK-like CAR T cell transition in CAR T cell dysfunction. Cell, 184(25), 6081-6100.e26. https://doi.org/10.1016/j.cell.2021.11.016

@article{5baef1da635a43b6b7d3cf2aee1c1075,

title = "An NK-like CAR T cell transition in CAR T cell dysfunction",

abstract = "Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.",

keywords = "CAR T cell, ID3, NK-like T cell, SOX4, T cell dysfunction, T cell exhaustion, cancer, cell transfer therapy, immunology, immunotherapy, pancreatic cancer, single-cell RNA-seq",

author = "Good, {Charly R.} and Aznar, {M. Angela} and Shunichiro Kuramitsu and Parisa Samareh and Sangya Agarwal and Greg Donahue and Kenichi Ishiyama and Nils Wellhausen and Rennels, {Austin K.} and Yujie Ma and Lifeng Tian and Sonia Guedan and Alexander, {Katherine A.} and Zhen Zhang and Rommel, {Philipp C.} and Nathan Singh and Glastad, {Karl M.} and Richardson, {Max W.} and Keisuke Watanabe and Tanyi, {Janos L.} and O'Hara, {Mark H.} and Marco Ruella and Lacey, {Simon F.} and Moon, {Edmund K.} and Schuster, {Stephen J.} and Albelda, {Steven M.} and Lanier, {Lewis L.} and Young, {Regina M.} and Berger, {Shelley L.} and June, {Carl H.}",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = dec,

day = "9",

doi = "10.1016/j.cell.2021.11.016",

language = "English",

volume = "184",

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Good, CR, Aznar, MA, Kuramitsu, S, Samareh, P, Agarwal, S, Donahue, G, Ishiyama, K, Wellhausen, N, Rennels, AK, Ma, Y, Tian, L, Guedan, S, Alexander, KA, Zhang, Z, Rommel, PC, Singh, N, Glastad, KM, Richardson, MW, Watanabe, K, Tanyi, JL, O'Hara, MH, Ruella, M, Lacey, SF, Moon, EK, Schuster, SJ, Albelda, SM, Lanier, LL, Young, RM, Berger, SL & June, CH 2021, 'An NK-like CAR T cell transition in CAR T cell dysfunction', Cell, vol. 184, no. 25, pp. 6081-6100.e26. https://doi.org/10.1016/j.cell.2021.11.016

TY - JOUR

T1 - An NK-like CAR T cell transition in CAR T cell dysfunction

AU - Good, Charly R.

AU - Aznar, M. Angela

AU - Kuramitsu, Shunichiro

AU - Samareh, Parisa

AU - Agarwal, Sangya

AU - Donahue, Greg

AU - Ishiyama, Kenichi

AU - Wellhausen, Nils

AU - Rennels, Austin K.

AU - Ma, Yujie

AU - Tian, Lifeng

AU - Guedan, Sonia

AU - Alexander, Katherine A.

AU - Zhang, Zhen

AU - Rommel, Philipp C.

AU - Singh, Nathan

AU - Glastad, Karl M.

AU - Richardson, Max W.

AU - Watanabe, Keisuke

AU - Tanyi, Janos L.

AU - O'Hara, Mark H.

AU - Ruella, Marco

AU - Lacey, Simon F.

AU - Moon, Edmund K.

AU - Schuster, Stephen J.

AU - Albelda, Steven M.

AU - Lanier, Lewis L.

AU - Young, Regina M.

AU - Berger, Shelley L.

AU - June, Carl H.

PY - 2021/12/9

Y1 - 2021/12/9

N2 - Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.

AB - Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.

KW - CAR T cell

KW - ID3

KW - NK-like T cell

KW - SOX4

KW - T cell dysfunction

KW - T cell exhaustion

KW - cancer

KW - cell transfer therapy

KW - immunology

KW - immunotherapy

KW - pancreatic cancer

KW - single-cell RNA-seq

UR - http://www.scopus.com/inward/record.url?scp=85120635876&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.11.016

DO - 10.1016/j.cell.2021.11.016

M3 - Article

C2 - 34861191

AN - SCOPUS:85120635876

SN - 0092-8674

VL - 184

SP - 6081-6100.e26

JO - Cell

JF - Cell

IS - 25

ER -

An NK-like CAR T cell transition in CAR T cell dysfunction

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Keywords

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