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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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“The design of combinational CAR-PSCA and CARMUC1-T cells, as proposed by Wei et al., showed excellent anti-NSCLC efficacy compared with the treatment of CAR-T cells targeting a single antigen (13).”
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Busselaar, J., Tian, S., van Eenennaam, H., & Borst, J. G. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.592569 · Cited by 57
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Guan, Q., Han, M., Guo, Q., Yan, F., Wang, M., Ning, Q., & Xi, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1204363 · Cited by 57
“However, NR4A-deficient CAR-T cells showed similar effects of Tox DKO CAR-T cells (Figure 4C) (Table 2) (30, 62).”
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InfluentialAll systems go: converging synthetic biology and combinatorial treatment for CAR-T cell therapy
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“Injection of NR4A1-deficient CAR-T cells into mice bearing a tumor can significantly inhibit tumor growth [61].”
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“Among downregulated genes, several genes associated with T cell exhaustion, suppression, and hypofunction ( NR4A2 , CREM , TGFB1 , METRNL ) 49–52 were identified.”
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“Forkhead box protein O1 (FoxO1), NFATc1, and nuclear receptor subfamily 4 group A (NR4A) have been reported to mediate the expression of PD-1 on exhausted CD8+ T cells (29-32).”
BackgroundT cell exhaustion is associated with antigen abundance and promotes transplant acceptance
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“24 25 In chronic immune responses in mice models, NR4A transcription factors are induced by NF-AT and promote dysfunctional/exhausted states of CD8 + T cells by suppressing cytokine expression via competing with AP-1/NF-kB and accelerating the expression of inhibitory receptors through directly…”
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“, 2020) and exhausted T cells in the tumor microenvironment (Chen et al., 2019; Liu et al., 2019), remains to be defined.”
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“Moreover, NR4A knockout or JUN overexpression showed excellent inhibitory effects on CAR-T cell exhaustion [3, 26].”
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“Naive-/memory-related TFs ( TCF7 , etc.) 23 and MXD4 , a suppressor of MYC , 24 were upregulated with KIT and IL7R acquisition, whereas effector/exhaustion-related TFs ( EGR1 , TOX2 and NR4A1 , etc.), 25,26 AP-1 TFs ( FOS and JUNB , etc.) 22 and anergy-related TFs ( EGR2 , etc.) 27 were downregulated with immune check…”
InfluentialEarly programming of CD8 + T cell response by the orphan nuclear receptor NR4A3
Odagiu, L., Boulet, S., Sousa, D. M. D., Daudelin, J., Nicolas, S., & Labrecque, N. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007224117 · Cited by 47
“This is similar to what has been recently reported for NR4A1 in CD4 T cells and for NR4A triple-deficient CD8 tumor-infiltrating lymphocytes (TILs) (33, 35).”
BackgroundResultInfluentialHierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK
Gallagher, M. P., Conley, J. M., Vangala, P., Garber, M. G., Reboldi, A., & Berg, L. J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2025825118 · Cited by 51
“ChIP assays utilizing a constitutively active NFAT mutant, in which NFAT is permanently nuclear, shows that NFAT cannot bind the IL-2 promoter without its AP-1 binding partner; in the absence of AP-1, IL-2 transcription is abrogated (40, 53).”
BackgroundMethodTuberculosis endotypes to guide stratified host-directed therapy
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Utility and Drawbacks of Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Lung Cancer
Kandra, P., Nandigama, R., Eul, B. G., Huber, M., Kobold, S., Seeger, W., Grimminger, F., & Savai, R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.903562 · Cited by 50
“In solid tumors, the NR4A transcription factor family plays an important role in T-cell exhaustion, which limits CAR-T cell function in solid tumors (85).”
BackgroundRelapse after CAR-T cell therapy in B-cell malignancies: challenges and future approaches
Gu, T., Zhu, M., Huang, H., & Hu, Y. (2022) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2200256 · Cited by 45
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“Furthermore, the NFAT-induced transcription factors EGR2 and NR4A1 that contribute to tolerance induction are also induced in exhaustion and, at least in the case of NR4A1, actively enforce the exhausted phenotype (110, 112, 144).”
BackgroundSchrödinger’s T Cells: Molecular Insights Into Stemness and Exhaustion
Gonzalez, N. M., Zou, D., Gu, A., & Chen, W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.725618 · Cited by 46
“Knocking out all three NR4As in CAR T cells promotes tumor regression and prolongs the survival of tumor-bearing mice (53).”
BackgroundTherapeutic potential of NR4A1 in cancer: Focus on metabolism
Deng, S., Chen, B., Huo, J., & Liu, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.972984 · Cited by 46
“The NR4A receptors are also associated with the activation of T cell, which involving in cancer immunotherapy (15).”
BackgroundExhausted T cells hijacking the cancer-immunity cycle: Assets and liabilities
Brunell, A. E., Lahesmaa, R., Autio, A. K., & Thotakura, A. K. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1151632 · Cited by 46
“PD-1TCF-1 precursor exhausted T cells have stem cell-like properties as they have the capacity to proliferate, self-renew and further produce progeny populations of exhausted T cells, including terminally exhausted less proliferative PD-1TCF-1T cells (Figure 1) (11, 14).”
BackgroundSite-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies
Dabiri, H., Kozani, P. S., Habibi‐Anbouhi, M., Godarzee, M. M., Haddadi, M. H., Basiri, M., Ziaei, V., Sadeghizadeh, M., & Saffar, E. H. (2023) · Biomarker Research · doi:10.1186/s40364-023-00509-1 · Cited by 45
“NR4A Disruption CD8+ T cells CAR T cells that are lacking all three Nr4a TFs (Nr4aTKO) promote tumor regression and prolong the survival rate of tumor-bearing mice and reduce hyporesponsiveness of CD8+ T cells [58]”
BackgroundSynthetic manipulation of the cancer-immunity cycle: CAR-T cell therapy
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Reversing Post-Infectious Epigenetic-Mediated Immune Suppression
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“NR4A family member genes exhibit greater chromatin accessibility in exhausted tumor infiltrating lymphocytes (62).”
BackgroundAltered cancer metabolism and implications for next-generation CAR T-cell therapies
Ramapriyan, R., Vykunta, V. S., Vandecandelaere, G., Richardson, L. G., Sun, J. M., Curry, W. T., & Choi, B. D. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108667 · Cited by 48
IL-4 drives exhaustion of CD8+ CART cells
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T cell-based cancer immunotherapy: opportunities and challenges
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Novel antigens of CAR T cell therapy: New roads; old destination
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RNA Therapeutics for Improving CAR T-cell Safety and Efficacy
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Common gamma chain cytokines and CD8 T cells in cancer
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Epigenetics and CD8+ T cell memory*
Montacchiesi, G., & Pace, L. (2021) · Immunological Reviews · doi:10.1111/imr.13057 · Cited by 43
Landscapes and mechanisms of CD8+ T cell exhaustion in gastrointestinal cancer
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“Transcription factor NR4a has also been reported to drive Tex via orchestrating epigenetic changes in CD8 tumor-infiltrating lymphocytes (TIL) and chimeric antigen receptor (CAR) T cells (82, 88, 89).”
BackgroundProgress and pitfalls of gene editing technology in CAR-T cell therapy: a state-of-the-art review
Moradi, V., Khodabandehloo, E., Alidadi, M., Omidkhoda, A., & Ahmadbeigi, N. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1388475 · Cited by 42
“These negative regulators include Cytokine-inducible SH2-containing protein (CISH) (126), DNA methyltransferase 3 alpha (DNMT3A) (127), Cbl-b (128), nuclear receptor transcription factors NR4A (129), Diacylglycerol kinases (130), adenosine A2A receptor (131) ID3, SOX4 (132), TGF-b receptor II (133), and protein tyrosi…”
BackgroundHow metabolism bridles cytotoxic CD8+ T cells through epigenetic modifications
Acker, H. H. V., Ma, S., Scolaro, T., Kaech, S. M., & Mazzone, M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.03.006 · Cited by 39
“Thus, NR4A has been identified as being crucial for the epigenetic and transcriptional program of CD8 T cell exhaustion [21,22].”
BackgroundYang, K., Zhao, Y., Sun, G., Zhang, X., Cao, J., Shao, M.-C., Liang, X., & Wang, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1081546 · Cited by 42
“It binds to PD-L1 expressed by target cells and sends an inactivating signal to T cells, thereby inhibiting the immune activity of T cells (12, 99, 100).”
BackgroundThe Interplay between T Cells and Cancer: The Basis of Immunotherapy
Chen, C., Liu, X., Chang, C., Wang, H. Y., & Wang, R. (2023) · Genes · doi:10.3390/genes14051008 · Cited by 42
“Nr4a TKO CAR+ TILs exhibited phenotypic, genotypic, and epigenetic profiles that were similar to those of functional effector CD8+ T cells, further highlighting the significant role that NR4A family members play in T-cell-intrinsic exhaustion [115].”
BackgroundInfluentialA Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives
Montoya, M., Gallus, M., Phyu, S. M., Haegelin, J., de Groot, J., & Okada, H. (2024) · Cells · doi:10.3390/cells13090726 · Cited by 43
“Research has displayed that exhausted CD8+ T cells from cancer patients express high levels of three NR4A transcription factors, which are initiated by NFAT [169,170].”
BackgroundLith, S. C., van Os, B. W., Seijkens, T. T. P., & de Vries, C. J. M. (2020) · European Journal of Immunology · doi:10.1002/eji.202048869 · Cited by 39
CRISPR/Cas9 system: recent applications in immuno-oncology and cancer immunotherapy
Chen, C., Wang, Z., & Qin, Y. (2023) · Experimental Hematology and Oncology · doi:10.1186/s40164-023-00457-4 · Cited by 42
“Additionally, inhibition of NR4A transcriptional factor using CRISPR/ Cas9 results in the downregulation of PD1 and TIM-3 [108].”
MethodSmirnov, S., Mateikovich, P., Samochernykh, K. A., & Shlyakhto, E. V. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1335424 · Cited by 42
“CAR-T cells with triple knockout of three NR4A transcription factors prolonged the survival of tumor-bearing mice (86).”
BackgroundNR4A1 Acts as a Novel Regulator of Platelet Activation and Thrombus Formation
Liu, W., Li, G., Shi, J., Gao, Y., Fang, P., Zhao, Y., Zhong, F., Guo, X. H., Lyu, Y., Da, X., et al. (2025) · Circulation Research · doi:10.1161/circresaha.124.325645 · Cited by 38
“It influences the development and function of T cells in the immune system, 15–17 acts as either a tumor suppressor or promoter depending on the context of cancer, 18 plays an integral role in neuronal homeostasis and neuroprotection, 19 attenuates fibrosis by acting as an inhibitor of TGF-β…”
Garrido-Castro, A. C., Kim, S. E., Li, T., Desrosiers, J., Nanda, R., Abdou, Y., Clark, A. S., Sacks, R. L., O'Connor, T. P., Sinclair, N. F., et al. (2024) · Annals of Oncology · doi:10.1016/j.annonc.2026.06.012 · Cited by 37
Dimitri, A. J., Baxter, A. E., Chen, G. M., Hopkins, C. R., Rouin, G. T., Huang, H., Kong, W., Holliday, C., Wiebking, V., Bartoszek, R. L., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp9371 · Cited by 42
Xu, X., Chen, H., Ren, Z., Xu, X., Wu, W., Yang, H., Wang, J., Zhang, Y., Zhou, Q., Li, H., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.11.005 · Cited by 44
Fu, Z., Dean, J. W., Xiong, L., Dougherty, M. W., Oliff, K. N., Chen, Z. E., Jobin, C., Garrett, T. J., & Zhou, L. (2021) · Nature Communications · doi:10.1038/s41467-021-24755-9 · Cited by 36
Function and evolution of the prototypic CD28ζ and 4-1BBζ chimeric antigen receptors
Feucht, J., & Sadelain, M. (2020) · Immuno-Oncology Technology · doi:10.1016/j.iotech.2020.09.001 · Cited by 42
“The enhanced effector function of Nr4a triple knockout CAR T cells was associated with increased cytokine production, downregulation of inhibitory receptors, and strong enrichment in accessible chromatin for binding motifs of transcription factors involved in effector function.(91) 1928z CAR T cells double deficient i…”
BackgroundFlavonoids Quercetin and Kaempferol Are NR4A1 Antagonists and Suppress Endometriosis in Female Mice
Zhang, L. J., Mohankumar, K., Martin, G., Mariyam, F., Park, Y., Han, S. J., & Safe, S. H. (2023) · Endocrinology · doi:10.1210/endocr/bqad133 · Cited by 36
Engineering mtDNA Deletions by Reconstituting End-Joining in Human Mitochondria
Fu, Y., Land, M., Kavlashvili, T., Cui, R., Kim, M., DeBitetto, E., Lieber, T., Ryu, K. W., Choi, E., Masilionis, I., et al. (2024) · Cell · doi:10.1016/j.cell.2025.02.009 · Cited by 36
Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis
Ashouri, J. F., Hsu, L., Yu, S., Rychkov, D., Chen, Y., Cheng, D. A., Sirota, M., Hansen, E., Lattanza, L. L., Zikherman, J., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1904271116 · Cited by 35
“This is consistent with a recent report demonstrating that NR4A gene expression positively correlated with PDCD1 (PD-1), TIGIT, and other inhibitory receptors in the setting of chronic antigen stimulation as part of a T cell-intrinsic program of hyporesponsiveness (43).”
ResultHiwa, R., Nielsen, H. V., Mueller, J. L., Mandla, R., & Zikherman, J. (2021) · JCI Insight · doi:10.1172/jci.insight.151005 · Cited by 34
“Antagonizing NUR77 and perhaps other NR4A family 559 members could have applications for cancer immunotherapy (9).”
BackgroundMethodInfluentialRegulatory effects of IRF4 on immune cells in the tumor microenvironment
Lu, J., Liang, T., Li, P., & Yin, Q. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1086803 · Cited by 36
“Specifically, overexpressed IRF4 binding with AP1 family members or NFAT leads to an overabundance of IRF4/AP1 complexes or NFAT homodimers that are recruited to specific DNA sites to open multiple exhaustion-related chromatin regions, including inhibitory receptors, such as PD1, T-cell immunoglobulin and mucin domain…”
BackgroundLong-term caloric restriction ameliorates T cell immunosenescence in mice
Asami, T., Endo, K., Matsui, R., Sawa, T., Tanaka, Y., Saiki, T., Tanba, N., Haga, H., & Tanaka, S. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111710 · Cited by 37
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) · Nature Communications · doi:10.1038/s41467-024-53997-6 · Cited by 37
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Targeting Nuclear Receptors for Cancer Therapy: Premises, Promises, and Challenges
Yang, Z., Gimple, R. C., Zhou, N., Zhao, L., Gustafsson, J.-Α., & Zhou, S. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.11.007 · Cited by 36
Wells, A. C., Hioki, K. A., Angelou, C. C., Lynch, A. C., Liang, X., Ryan, D. J., Thesmar, I., Zhanybekova, S., Žuklys, S., Ullom, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40959-7 · Cited by 35
“Therefore, the molecular mechanisms that regulate these processes are the subject of intensive research 17 – 20 .”
Merlin, J. P. J., & Abrahamse, H. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117516 · Cited by 35
Li, Z., Jiang, C., & Yuan, Y. (2019) · PLoS ONE · doi:10.1371/journal.pone.0216834 · Cited by 34
Nanoparticle Amplification Labeling for High-Performance Magnetic Cell Sorting
Wang, Z., Wang, H., Lin, S., Ahmed, S. U., Angers, S., Sargent, E. H., & Kelley, S. O. (2022) · Nano Letters · doi:10.1021/acs.nanolett.2c01018 · Cited by 34
PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy
Wang, L., Xiao, Y., Luo, Y., Master, R. P., Mo, J., Kim, M., Liu, Y., Maharjan, C. K., Patel, U. M., De, U., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20231519 · Cited by 36
“We also observed (Chen et al., 2019a; Liu et al., 2019).”
BackgroundHao, J., Li, R., Zhao, X., Liu, X., Chen, X., Xie, T., Li, X., Yao, C., Sun, Q., Wei, K., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114301 · Cited by 35
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Analysis of causes for poor persistence of CAR-T cell therapy in vivo
Kong, Y., Tang, L. Y., You, Y., Li, Q., & Zhu, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1063454 · Cited by 36
“CAR-T cells lacking the NR4A1, NR4A2 and NR4A3 transcription factors have downregulated expression of PD-1 and TIM3 and stronger antitumor effects (56).”
BackgroundLing, K., Dou, Y., Yang, N., Deng, L., Wang, Y., Li, Y., Yang, L., Chen, C., Jiang, L., Deng, Q., et al. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.07.007 · Cited by 34
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“Treatment of tumor-bearing mice with T cells expressing chimeric antigen receptors lacking all three NR4A receptors in vivo results in tumor regression and prolonged survival (12).”
BackgroundMethodForoutan, M., Molania, R., Pfefferle, A., Behrenbruch, C., Scheer, S., Kallies, A., Speed, T. P., Cursons, J., & Huntington, N. D. (2021) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-21-0137 · Cited by 35
“limit the function of chimeric antigen receptor (CAR) T cells in solid tumours [67].”
BackgroundLiu, G., Zhang, Q., Liu, G., Li, D., Zhang, L., Gu, Z., Tian, H., Zhang, Y., & Tian, X. (2021) · Experimental Cell Research · doi:10.1016/j.yexcr.2021.112886 · Cited by 32
Tanaka, H., Miyama, R., Sakurai, Y., Tamagawa, S., Nakai, Y., Tange, K., Yoshioka, H., & Akita, H. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13122097 · Cited by 34
“Representatives of such modifications include an enhancement in cytotoxic activity by avoiding T cell exhaustion [7], improved safety profiles by removing inherent T cell receptors from the T cell population [8], and the establishment of universal CAR-T cells by eliminating major histocompatibility complexes from thei…”
BackgroundRiegel, D., Romero-Fernández, E., Simon, M., Adenugba, A., Singer, K., Mayr, R., Weber, F., Kleemann, M., Imbusch, C. D., Kreutz, M. P., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.029 · Cited by 35
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Cytokine signaling in chimeric antigen receptor T-cell therapy
Kagoya, Y. (2023) · International Immunology · doi:10.1093/intimm/dxad033 · Cited by 31
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“In addition, the cell-intrinsic programs of CAR-T cells also play an important role in the functional impairment of CAR-T cells and may lead to therapeutic failure [5, 9-12].”
BackgroundUnlocking T cell exhaustion: Insights and implications for CAR-T cell therapy
Xiong, D., Yu, H., & Sun, Z. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.04.022 · Cited by 31
“Additionally, combined knockout of Nr4a1 , Nr4a2 and Nr4a3 reprogrammed the epigenetic landscape of tumor-infiltrating CAR-T cells to promote cytotoxicity and tumor con-trol 100,101 .”
BackgroundAdvances in Melanoma: From Genetic Insights to Therapeutic Innovations
Valdez-Salazar, F., Rio, L. A. J.-D., Padilla‐Gutiérrez, J. R., Valle, Y., Muñóz-Valle, J. F., & Valdés‐Alvarado, E. (2024) · Biomedicines · doi:10.3390/biomedicines12081851 · Cited by 35
“Nonetheless, adoptive cell therapies are associated with significant challenges, including high costs, complex manufacturing processes, and potential severe side effects such as cytokine release syndrome and neurotoxicity [241–243].”
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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