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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MethodInfluential
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Wang, D., Prager, B. C., Gimple, R. C., Aguilar, B., Alizadeh, D., Tang, H., Lv, D., Starr, R., Brito, A., Wu, Q., et al. (2023) · doi:10.1158/2159-8290.c.6549389.v1
Data from The Ratio of Exhausted to Resident Infiltrating Lymphocytes Is Prognostic for Colorectal Cancer Patient Outcome
Foroutan, M., Molania, R., Pfefferle, A., Behrenbruch, C., Scheer, S., Kallies, A., Speed, T. P., Cursons, J., & Huntington, N. D. (2023) · doi:10.1158/2326-6066.c.6550434.v1
Supplementary Table 2 from CRISPR Screening of CAR T Cells and Cancer Stem Cells Reveals Critical Dependencies for Cell-Based Therapies
Wang, D., Prager, B. C., Gimple, R. C., Aguilar, B., Alizadeh, D., Tang, H., Lv, D., Starr, R., Brito, A., Wu, Q., et al. (2023) · doi:10.1158/2159-8290.22540475.v1
The pathogenetic significance of exhausted T cells in a mouse model of mature B cell neoplasms
Shibamiya, A., Miyamoto‐Nagai, Y., Koide, S., Oshima, M., Rizq, O., Aoyama, K., Nakajima‐Takagi, Y., Kato, R., Kayamori, K., Isshiki, Y., et al. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03447-x
NR4A3 deficiency in CD8 + T cells improves adoptive T cell therapy of cancerPreprint
Odagiu, L., Mezrag, S., Sousa, D. M. D., Boulet, S., & Labrecque, N. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.21.537841
Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer ImmunotherapyPreprint
Wang, L. A., Xiao, Y., Luo, Y., Master, R. P., Mo, J., Kim, M., Liu, Y., Patel, U. M., Li, X., Shaffer, D. R., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.09.552650
HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cellsPreprint
Wu, H., Zhao, X., Hochrein, S. M., Eckstein, M., Gubert, G. F., Knöpper, K., Mansilla, A. M., Öner, A., Doucet-Ladevèze, R., Schmitz, W., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.31.555662
Nur77 Inhibit β-catenin Expression to Mediate Hepatoblastoma Progression and Therapeutic Effect of CisplatinPreprint
Zhou, J., Liu, X., Yin, H., Zhou, Y. F., Xu, Z., Zhou, K., Li, T., Fang, Y., & Shen, Q. (2023) · Research Square · doi:10.21203/rs.3.rs-3350840/v1
442-H IL-21 on/off switch CAR-T enhance anti-tumor effects by epigenetic and transcriptional regulation
Seo, H. (2023) · doi:10.1136/jitc-2023-sitc2023.0442-h
Self-citation
Transcription Factor-target Relationships Complicated by Knockout Analysis
Dai, Z. (2023) · International Conference on Bioinformatics and Biomedical Technology (ICBBT) · doi:10.1145/3608164.3608176
“Over the past few years, such experiments on transcription factor (TF) knockout helped identify TF potential regulatory targets [8-11].”
Background
T cell exhaustion and challenges of CAR-T cell therapy for solid tumors
Kuramitsu, S., Yamaguchi, J., Nohira, S., Ohno, M., Fujita, M., & Saito, R. (2024) · Japanese Journal of Transplantation and Cellular Therapy · doi:10.7889/tct-23-029
The transcription factor IRF-5 is essential for the metabolic rewiring of CD8 T cells during chronic infectionPreprint
Mai, L. T., Swaminathan, S., Nguyen, T. H., Charpentier, T., Loucif, H., Carmona‐Pérez, L., Lamarre, A., Heinonen, K. M., Fritz, J. H., & Stäger, S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.29.577789
Cellular reprogramming by protein degradation: The next frontier in cancer immunotherapy
Ehinger, E., & Rao, A. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.01.004
Self-citation
An Update on the Treatment Strategy for Non-small Cell Lung Cancer: A Current Scenario and Future Perspective
Rajendran, R., & Mathaiyan, J. (2024) · Current Cancer Therapy Reviews · doi:10.2174/0115733947276538240129053601
NR4A3 deficiency ameliorates contact hypersensitivity and exacerbates psoriasis by regulating gene expression in dendritic cellsPreprint
Katagiri, M., Ito, N., Nagata, K., Nakano, S., Minamikawa, N., Yamashita, N., Takahashi, M., Kurihara, M., Nagaoka, M., Ando, M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.20.581116
Self-citation
Cancer Immunotherapy: A Systemic Review
Bokshi, S. K., Biswas, K. R., & Chowdhury, A. K. (2024) · Archives of Oncology and Cancer Therapy · doi:10.22259/2638-5074.0401004
Transcriptional control of central T cell tolerance by NR4A family nuclear receptorsPreprint
Nielsen, H. V., Mueller, J. L., Hiwa, R., Yang, L., Proekt, I., Rackaityte, E., Aylard, D. A., Scharer, C. D., Anderson, M. S., Au‐Yeung, B. B., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.19.594881
TCR Affinity and Signaling During Thymocyte Selection
May, J. F., Joannou, K., & Baldwin, T. A. (2024) · Elsevier eBooks · doi:10.1016/b978-0-128-24465-4.00013-2
YTHDF2 upregulation and relocation dictate CD8 T cell polyfunctionality in tumor immunityPreprint
Zhang, H., Luo, X.-J., Yang, W., Wu, Z., Zhao, Z., Pei, X., Zhang, X., Chen, C., Lei, J. H., Shi, Q., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.11.603088
Self-citation
Progress and Prospects in CRISPR Genome Engineering Nucleases
Surendranath, K., Akram, K., Kanagaraj, R., Savash, M., Khan, S., Pantuzcek, J., Karri, M., Guha, S., Rangan, S. L., Kour, E., et al. (2024) · Springer eBooks · doi:10.1007/978-981-97-1777-4_4
The role of cellular persistence in CAR T cell therapy
Menkhoff, V. D., Bernhard, S., Michaelides, S., Stock, S., & Kobold, S. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-14064-8.00029-1
Acquisition of an immunosuppressive microenvironment after CAR-T therapy drives T-cell dysfunction and resistancePreprint
Ponzo, M., Drufuca, L., Buracchi, C., Sindoni, M. M., Nucera, S., Bugarin, C., Bason, R., Rossetti, G., Bonnal, R. J. P., Meli, C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.20.629119
Phenotypic Heterogeneity of Dysfunctional Natural Killer Cells During Chronic Infection or Cancer
Pouxvielh, K., Marotel, M., Rousseaux, N., Picq, L., Benezech, S., Nombel, A., Kern, N., Marçais, A., & Walzer, T. (2025) · Springer eBooks · doi:10.1007/978-3-662-68816-8_30-1
Single Cell RNA-Seq Analysis Reveals Similarities Between Colorectal, Liver and Lung T Cells’ Populations
Saada, B., Qu, C., Siga, E., & Jing, Z. (2025) · Communications in computer and information science · doi:10.1007/978-981-96-1907-8_2
Dissecting the causal role of immunophenotypes in brain meningioma risk: A Mendelian randomization study
Zhu, X., Wang, Y., Liu, Z., Zhang, X., Zhang, S., Pang, B., & Zhu, S. (2025) · Medicine · doi:10.1097/md.0000000000042678
Nurr1 modulators – a patent review (2019–present)
Egner, M., & Merk, D. (2025) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2025.2516780
Bibliometric analysis of immunotherapy in treatment of uveal melanoma
Chen, W., Zhang, H., Xiao, D., Bai, M., Luo, Y., Li, X., & Long, B. (2025) · Medicine · doi:10.1097/md.0000000000042932
“[52,53] CARs are receptors that recognize tumor-associated antigens and consist of 2 primary components: recombinant immunoglobulin variable sequences forming the extracellular domain, and cytoplasmic sequences containing T cell receptor (TCR) signaling motifs as well as motifs derived from T cell…”
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
Zander, R., & Cui, W. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00278-7
Pretreatment with alendronate augments lipid A-induced IFN-β production via upregulation of cGAS expression
Watanabe, S., Kiyoura, Y., & Tamai, R. (2025) · Pharmacological Reports · doi:10.1007/s43440-025-00773-y · Cited by 1
“Nur77 also inhibits the activation of nuclear factor-κB (NF-κB), which plays an important role in the production of proinflammatory cytokines in the nucleus [ 44].”
Epigenetic Regulation of CD8 T Cell Differentiation
Passos, T. O., Oliveira, J. P., Melo, G. A., Calôba, C., & Pereira, R. M. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00283-0
Common origin for effector and regulatory follicular and tissue-Adapted CD4+ T cells in Non-Small Cell Lung CancerPreprint
Tosello, J., Richer, W., Missolo-Koussou, Y., Bonnin, E., Lemoine, S., Pretti, M. A. M., Ramos, R. N., Denizeau, J., Baulande, S., Bohec, M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.17.674622
NR4A nuclear receptor expression in human macrophages mediates apoptosis and controls Mycobacterium tuberculosis growth
Simper, J., Jarvis, N., Pahari, S., Ortega, D., Azad, A., Safe, S. H., Arnett, E., & Schlesinger, L. S. (2025) · The Journal of Immunology · doi:10.1093/jimmun/vkaf252
MCT8 Modulates Metabolite Uptake and T-cell Exhaustion to Promote Immunosuppression and Tumor Progression in Hepatocellular Carcinoma
Bi, B., Tang, L., Liang, R., Wu, H., Huang, Q., & Pan, L. Q. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-25-0564
CD7 drives CD8 T cell exhaustion during chronic viral infection
Reisch, K. M., Scherer, A., Bartell, R., Santana, F., Shao, P., Butler, N. S., & Zander, R. (2025) · The Journal of Immunology · doi:10.1093/jimmun/vkaf283.1625
A nucleotide regulates NR4A1 status in gastric cancer
Ma, Q., Yin, M., & Lei, Q. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.11.012
Enhanced anti-liver tumor efficacy of chimeric antigen receptor-T cells via SATB1 modulation
Zhang, L., Cheng, C., Bi, X., Cao, J., Li, X., & Zhao, T. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-08307-3
“Recent efforts to combat T cell exhaustion have focused on modulating transcriptional regulators such as c-Jun [15], NR4A family members [16, 17], BATF (from the AP-1 family) [18, 19], FOXO1 [20, 21], Id2 [22], and Stat5 [23].”
CD9-positive tumor-associated macrophages promote renal cell carcinoma progression by activating the orphan nuclear receptor Nor1/Nr4a3
Pan, P., Li, S., Yin, W., Wang, P., Ma, T., Bi, Z., Song, J., Song, X., Huang, X., Hao, J., et al. (2025) · Cancer Cell International · doi:10.1186/s12935-025-04060-x
“Some other findings establish NR4A3 factors as key drivers of CAR-T hyporesponsiveness in solid tumours and point to NR4A inhibition (genetic deletion, siRNA, or small-molecule antagonists) as a promising strategy to enhance CAR-T therapy for solid cancers [30].”
Additional file 1 of Modulating tumor infiltrating myeloid cells to enhance bispecific antibody-driven T cell infiltration and anti-tumor response
Park, J. A., Wang, L., & Cheung, N.-K. V. (2021) · Figshare · doi:10.6084/m9.figshare.16590464
Engineering IL-21 secretion in T cells using druggable ligand-responsive stabilized domains
Kim, D. H., Lee, S. H., Ahn, T., Kim, H.-Y., Kim, K., & Seo, H. (2025) · Scientific Reports · doi:10.1038/s41598-025-32677-5
Self-citation
Transcriptional and Epigenetic Regulation of T Cell States in Cancer
Ma, S., Hargreaves, D. C., & Kaech, S. M. (2026) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061325-042744
Synthetic Hybrid Receptors for Safer and Programmable T Cell TherapyPreprint
Foisey, M. G., Garcia, J. M., Li, X., Yang, X., Hilburger, C. E., Thienpont, C., Chaves-Martinez, A., Belkaya, S., Truong, T., Zhu, I., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.22.701150 · Cited by 1
“Common strategies include constitutive co-expression of proinflammatory cytokines (“armored” CARs), transcription factors, or targeted gene knockouts to enhance effector function and persistence 6-13 .”
Transcriptional and epigenetic control of human naïve CD8+ T cell activation
Hu, Y., Du, Y., Chen, X., Li, Y., & Yang, C. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1749526
Intermittent Tacrolimus Treatment Delays CD8+ Tumor‐Infiltrating Lymphocyte Exhaustion and Enhances PD1 Blockade Therapy in Melanoma‐Bearing Mice
Chen, D., Feng, S., Chen, Z., Weng, Z., Zhang, S., Lin, J., & Wang, Z. (2026) · Journal of Immunology Research · doi:10.1155/jimr/8444562

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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