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NR4A transcription factors limit CAR T cell function in solid tumours
Open accessAbstract
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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“Because Nr4a2 is highly related to Nr4a1 and has been found to promote T cell exhaustion (33-35),”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [34]
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“T cell exhaustion also limits the efficacy of chimeric antigen receptor (CAR) T cell therapy against solid tumours14–17.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [15]
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“NFAT-induced transcription factors, including NR4A and TOX, drive T cell exhaustion/dysfunction44–47.”
From Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma (2023) · cites this paper as [44]
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“59 The removal of intracellular regulators like PTPN2 also increases the expansion, effector function, and iScience Review resistance to the immunosuppressive TME of CAR-T cells, making them even more effective as a treatment.”
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“Notably, NR4A1 is pivotal for inducing T effector cell dysfunction and fostering an immunosuppressive micro-environment [30, 31], suggesting that ANXA1 + CD8 + T cells are associated with immune suppression.”
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The transcription factor IRF8 drives tumor-specific exhaustion in CD8+ T cells
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“Among the central regulators of this state, several families of transcription factors (TFs) play a dominant function, including TOX (Alfei et al., 2019; Khan et al., 2019; Scott et al., 2019), NFAT (Martinez et al., 2015; Tille et al., 2023), and NR4A (Chen et al., 2019) families.”
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“185,186 The TOX/NR4A axis also reshapes chromatin accessibility away from NF-κ B-and AP-1-associated effector programmes.”
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Mechanisms of Resistance and Relapse After CAR-T Cell Therapy
Selli, M. E., Dalal, P., Neelapu, S. S., & Singh, N. (2022) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-030-87849-8_12 · Cited by 2
Intermittent administration of tacrolimus enhances anti-tumor immunity in melanoma-bearing mice
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Self-citationA Novel Immune-Prognosis Index Predicts the Benefit of Lung Adenocarcinoma Patients
Bai, Y., Pei, Y., Xia, L., Ma, L., & Deng, S. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.818170 · Cited by 2
A Novel Biological Nano Confinement Inhibits Cancer Metastasis
Lu, S., Zhao, Z., Lv, Z., & Yang, J. (2022) · ONCOLOGIE · doi:10.32604/oncologie.2022.025144 · Cited by 2
“What’s the reason? A previous study suggests that CAR-T therapy has a drawback: T cells entering solid tumors may stop working because of a ‘T-cell failure’ (T cell exhaustion) phenomenon [42].”
BackgroundCAR T-Cell Therapy in Solid Tumors: Current Review and Future Perspectives
Zheng, J. (2023) · Highlights in Science Engineering and Technology · doi:10.54097/hset.v54i.9841 · Cited by 3
“For example, c-Myb promotes T Cell formation [90], TOX and nuclear receptor transcription factors NR4A1, NR4A2 and NR4A3, inhibit T cell differentiation and function [30-32, 91, 92] Overexpression of c-Jun in CAR-T cells increases their functional capacity and reduces terminal T cell differentiation[93].”
BackgroundGenome Editing for Engineering the Next Generation of Advanced Immune Cell Therapies
de Lima, S. C. G., Fantacini, D. M. C., Furtado, I. P., Rossetti, R., Silveira, R. M., Covas, D. T., & de Souza, L. E. B. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-33325-5_6 · Cited by 2
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“Blocking LAG-3 has shown promise in rejuvenating exhausted T-cells and enhancing immune responses against infections [120] .”
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Immunosuppressive regulatory cells in cancer immunotherapy: restrain or modulate?
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“In addition, Chen et al., found that tumour-bearing mice treated with CAR T cells expressing small interfering RNA (siRNA) to inhibit Nr4a showed pronounced tumour regression and decrease of Tregs in the TME compared to tumour-bearing mice adoptively transferred with control CAR T cells [115].”
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Special Issue “The Promising Future of CAR-Based Therapies: A Matter of Molecular Details”
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“Additionally, transcriptional negative regulators such as Cb1-b [24], PTP1B [25], SOX4, and ID3 [26], and NR4A [27], have been identified as key factors driving exhaustion as their deletion enhances T cell effector functions [27,28].”
Adoptive CD8+ T cell therapy generates immunological memory to inhibit melanoma metastasis.
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Lessons from transmissible cancers for immunotherapy and transplant
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Orthogonal engineering of synthetic T cell states to enhance cancer immunotherapy
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PTPN1/2 inhibition induces highly functional terminal effector CD8 T cells through autocrine IL-10Preprint
Pérez‐Quintero, L., Poirier, A., Córdova, Z. M., Feng, C.-H., Aubry, I., Carli, C., Kamyabiazar, S., Pacis, A., Zolotarov, Y., Pike, K.-A., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.17.537264 · Cited by 2
“Indeed, dKO cells also showed increased upregulation of the three members of the transcription factor family NR4A (Figure 7E) in dKO cells over all the other genotypes analyzed, which is associated with the establishment of exhaustion in CD8 T cells [78].”
BackgroundWang, A. Z., Mashimo, B. L., Schaettler, M. O., Sherpa, N. D., Leavitt, L. A., Livingstone, A. J., Khan, S. M., Mao, L., Anzaldua-Campos, M. I., Bradley, J. D., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.25.554678 · Cited by 2
“T cell function, as triple knock out (TKO) of the NR4A1, NR4A2, and NR4A3 transcription factors significantly increased the effector function of CAR T cells in vivo (48).”
BackgroundHong, C., Choi, Y. H., Wald, D. N., & Hwang, T. H. (2023) · Regular and Young Investigator Award Abstracts · doi:10.1136/jitc-2023-sitc2023.1199 · Cited by 2
Proteome-wide base editor screens to assess phosphorylation site functionality in high-throughputPreprint
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“GZMB is the major effector molecule of the cytotoxic program 74 and NR4As have been shown to be drivers of T cell exhaustion 75,76 .”
BackgroundNR4A1 limits CD8 + T Cell effector responses and protection in tuberculosisPreprint
Singhal, A., Fatima, S., Chen, Y., Smulan, L., Satish, B., Jameson, M., Saini, S., Johnson, C., Tay, A., Foo, S., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-8363336/v1 · Cited by 2
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“We observed a hierarchy of effect sizes in our adoptive transfer studies: Nr4a3 deletion provided the greatest anti-tumor benefit, followed by Nr4a2 , while Nr4a1 deletion had the smallest effect on tumor growth and survival( 6 ).”
InfluentialSelf-citationCharting a shared epigenetic pathway to CD8+ T cell dysfunction in infection and cancer
Sandor, K. D., Dániel, B., & Satpathy, A. T. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.05.020 · Cited by 1
The Functional Adaptability of Hyporesponsive T Cells and Its Impact on Transplant Outcomes
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“Studies have shown that CAR-T cells lacking NR4A1, NR4A2, and NR4A3 transcription factors have downregulated PD-1 and TIM3 expression and stronger anti-tumor effects [36].”
Background
Metadata
- 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
- Venue
- Nature
- Published
- 2019-02-27
- Volume
- 567
- Issue
- 7749
- Pages
- 530-534
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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