Cited by 874CAR-T cell therapy researchCancer Immunotherapy and BiomarkersNuclear Receptors and Signaling

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NR4A transcription factors limit CAR T cell function in solid tumours

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Chen, Joyce, López-Moyado, Isaac F., Seo, Hyungseok, Lio, Chan-Wang J., Hempleman, Laura J., Sekiya, Takashi, Yoshimura, Akihiko, Scott-Browne, James P., Rao, Anjana·2019·Nature

DOI 10.1038/s41586-019-0985-xPMC PMC6546093

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Abstract

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies 1,2. CAR T cells have been less effective against solid tumours 3-5, in part because they enter a hyporesponsive ('exhausted' or 'dysfunctional') state 6-9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19+ tumour-bearing mice. CD8+CAR+ tumour-infiltrating lymphocytes and CD8+ endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells)10-12. CD8+ T cells from humans with cancer or chronic viral infections 13-15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8+ effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy.

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Background
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“BA CCD19-28 Control sg1 CD19-28 MED12 sg49 CD45RO C C R 7 % T E M o f C D 8+ C A R + % T E M o f C D 4+ C A R + MED12 sg49 Control sg1 U M A P 1 UMAP2 2.33 1.33 18.178.2 3.00 4.44 76.915.6 0 20 40 60 80 100 0 20 40 60 80 100 E Glycolysis MTORC1 signaling NES = 1.73 FDR = 0.003 NES = 1.57 FDR = 0.0110 0.35 Control sg1…”
BackgroundInfluential
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“Interestingly, in comparison to wild-type CAR T cells, the transfer of NR4A1, NR4A2, and NR4A3 triple knockout CAR T cells to tumor-bearing mice decreased the proportion of highly exhausted CAR T cells among the tumor-infiltrating lymphocytes and led to a better prognosis [57].”
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Background
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BackgroundInfluential
The current state and future of T-cell exhaustion research
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Background
Genetic ablation of PRDM1 in antitumor T cells enhances therapeutic efficacy of adoptive immunotherapy
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Background
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Background
The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion
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BackgroundInfluential
Advancing CAR T cell therapy through the use of multidimensional omics data
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Authors: Chen, J., López-Moyado, I. F., Seo, H., Lio, C.-W. J., Hempleman, L. J., Sekiya, T., Yoshimura, A., Scott-Browne, J. P., & Rao, A.
Affiliations: La Jolla Institute for Immunology (US)
National Center for Global Health and Medicine (JP)
Keio University (JP)
Corresponding author: Chen, Joyce
Scott-Browne, James P.
Rao, Anjana
ORCID: Chen, Joyce
López-Moyado, Isaac F.
Seo, Hyungseok
Lio, Chan-Wang J.
Sekiya, Takashi
Yoshimura, Akihiko
Scott-Browne, James P.
Rao, Anjana
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-02-27
Volume: 567
Issue: 7749
Pages: 530-534
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-0985-x
PMC: PMC6546093
OpenAlex: W2917547201
Cited by: 874
References: 47
Citations by year: 2026: 136 · 2025: 127 · 2024: 122 · 2023: 134 · 2022: 101 · 2021: 121 · 2020: 93 · 2019: 40
FWCI: 37.10
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders: National Institutes of Health (1s10od016262-01)
Japan Society for the Promotion of Science (18H02673, 19H04822, 16KT0114, 17H06175, 16K15292)
National Institute of General Medical Sciences (T32GM007752)
National Institute of Allergy and Infectious Diseases (R01AI109842, R01AI048213, R56AI109842, R01AI040127)
National Institute of Dental and Craniofacial Research (U01DE028227)
National Center for Research Resources (S10RR027366)
Topics: Health Sciences › Medicine › Oncology › CAR-T cell therapy research
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords: Nur77, Nurr1, NOR-1, chimeric antigen receptor T cells, CD19, T cell exhaustion, solid tumors, chromatin accessibility, NFAT, PD-1, TIM-3, tumor-infiltrating lymphocytes, effector T cells, cancer immunotherapy, transcriptional reprogramming
MeSH terms: Receptors, Chimeric Antigen, Animals, Chromatin, DNA-Binding Proteins, Female, Humans, Male, Melanoma, Experimental, Mice, Inbred C57BL, Neoplasms, Receptors, Steroid, Receptors, Thyroid Hormone, Transcription Factors, Survival Rate, Lymphocytes, Tumor-Infiltrating, NF-kappa B, CD8-Positive T-Lymphocytes, Transcription Factor AP-1, Antigens, CD19, Adoptive Transfer, Gene Expression Profiling, Cell Line, Tumor, Mice, Nuclear Receptor Subfamily 4, Group A, Member 1, Nuclear Receptor Subfamily 4, Group A, Member 2

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NR4A transcription factors limit CAR T cell function in solid tumours

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