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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Nr4a2 is highly related to Nr4a1 and has been found to promote T cell exhaustion.
“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]
T cell exhaustion limits the efficacy of chimeric antigen receptor (CAR) T cell therapy against solid tumours.
“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]
NFAT-induced transcription factors, including NR4A and TOX, drive T cell exhaustion/dysfunction.
“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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ResultT Cell Dysfunction and Exhaustion in Cancer
Zhang, Z., Liu, S., Zhang, B., Qiao, L., Zhang, Y., & Zhang, Y. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00017 · Cited by 385 · see citing works
Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion
Gumber, D., & Wang, L. D. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103941 · Cited by 409 · see citing works
An NK-like CAR T cell transition in CAR T cell dysfunction
Good, C. R., Aznar, M. A., Kuramitsu, S., Samareh, P., Agarwal, S., Donahue, G., Ishiyama, K., Wellhausen, N., Rennels, A. K., Ma, Y., et al. (2021) · Cell · doi:10.1016/j.cell.2021.11.016 · Cited by 397 · see citing works
Androgen receptor activity in T cells limits checkpoint blockade efficacy
Guan, X., Polesso, F., Wang, C., Sehrawat, A., Hawkins, R. M., Murray, S., THOMAS, G. V., Caruso, B., Thompson, R. F., Wood, M. A., et al. (2022) · Nature · doi:10.1038/s41586-022-04522-6 · Cited by 396 · see citing works
CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?
Wagner, J., Wickman, E., DeRenzo, C. C., & Gottschalk, S. M. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.09.015 · Cited by 383 · see citing works
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“Among TFs, Irf4, Junb, Eomes, and Batf3 were depleted, while Tbx21 and Nr4a3 were modestly enriched, supporting previous demonstrations of their roles in exhaustion (Figure 2F, center) (Ataide et al., 2020; Chen et al., 2019; Paley et al., 2012; Seo et al., 2021).”
BackgroundEngineering the next-generation of CAR T-cells with CRISPR-Cas9 gene editing
Dimitri, A. J., Herbst, F., & Fraietta, J. A. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01559-z · Cited by 370 · see citing works
BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells
Seo, H., González‐Avalos, E., Zhang, W., Ramchandani, P., Yang, C., Lio, C. J., Rao, A., & Hogan, P. G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00964-8 · Cited by 353 · see citing works
Self-citationExhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy
Jiang, W., He, Y., He, W., Wu, G. S., Zhou, X., Sheng, Q., Zhong, W., Lu, Y., Ding, Y., Qi, L., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.622509 · Cited by 340 · see citing works
Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells
Dong, M. B., Wang, G., Chow, R. D., Ye, L., Zhu, L., Dai, X., Park, J. J., Kim, H. R., Errami, Y., Guzman, C. D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.044 · Cited by 330 · see citing works
“1194 Cell 178, 1189–1204, August 22, 2019 NR4A family members were found to regulate CAR-T potency against solid tumors (Chen et al., 2019).”
RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer
Sethna, Z. M., Guasp, P., Reiche, C., Milighetti, M., Ceglia, N., Patterson, E., Lihm, J., Payne, G., Lyudovyk, O., Rojas, L. A., et al. (2025) · Nature · doi:10.1038/s41586-024-08508-4 · Cited by 356 · see citing works
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“To test this concept, we transduced naive T cells with a second-generation CAR targeting human CD19 33 .”
InfluentialEpigenetic regulation of T cell exhaustion
Belk, J. A., Dániel, B., & Satpathy, A. T. (2022) · Nature Immunology · doi:10.1038/s41590-022-01224-z · Cited by 334 · see citing works
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Cancer organoids 2.0: modelling the complexity of the tumour immune microenvironment
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“Approaches to improve the differentiation of stem cell–like T cells are diverse, such as 4-1BB domain insertion, potassium stimulation, and transcription factor reprogramming (19, 22, 31, 32).”
BackgroundDu, B., Qin, J., Lin, B., Zhang, J., Li, D., & Liu, M. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.03.019 · Cited by 281 · see citing works
Challenges and new technologies in adoptive cell therapy
Zhang, P., Zhang, G., & Wan, X. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01492-8 · Cited by 271 · see citing works
“However, triple knockout of Nr4a (including Nr4a1, Nr4a2, and Nr4a3) in CAR-T cells promoted tumor regression and prolonged the survival of tumor-bearing mice [285].”
BackgroundPost-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy
Good, Z., Spiegel, J. Y., Sahaf, B., Malipatlolla, M. B., Ehlinger, Z. J., Kurra, S., Desai, M. H., Reynolds, W. D., Lin, A. W., Vandris, P., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01960-7 · Cited by 250 · see citing works
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Androgen conspires with the CD8 + T cell exhaustion program and contributes to sex bias in cancer
Kwon, H., Schafer, J. M., Song, N., Kaneko, S., Li, A., Xiao, T., Ma, A., Allen, C., Das, K., Zhou, L., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abq2630 · Cited by 243 · see citing works
Cellular networks controlling T cell persistence in adoptive cell therapy
Chan, J. D., Lai, J., Slaney, C. Y., Kallies, A., Beavis, P. A., & Darcy, P. K. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00539-6 · Cited by 242 · see citing works
Wnt signaling pathway in cancer immunotherapy
Zhou, Y., Jiang, X., Luo, H., Meng, X., Chen, M., & Zhu, D. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.10.034 · Cited by 238 · see citing works
Memory T cell, exhaustion, and tumor immunity
Ando, M., Ito, M., Srirat, T., Kondo, T., & Yoshimura, A. (2019) · Immunological Medicine · doi:10.1080/25785826.2019.1698261 · Cited by 226 · see citing works
Self-citation‘Stem-like’ precursors are the fount to sustain persistent CD8+ T cell responses
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Divergent clonal differentiation trajectories of T cell exhaustion
Dániel, B., Yost, K. E., Hsiung, S., Sandor, K. D., Xia, Y., Qi, Y., Hiam-Galvez, K. J., Black, M., Raposo, C. J., Shi, Q., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01337-5 · Cited by 226 · see citing works
Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity
Yan, C., Zheng, L., Jiang, S., Yang, H., Guo, J., Jiang, L., Li, T., Zhang, H., Bai, Y., Lou, Y., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.04.016 · Cited by 224 · see citing works
Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming
Bénéchet, A. P., De Simone, G., Di Lucia, P., Cilenti, F., Barbiera, G., Le Bert, N., Fumagalli, V., Lusito, E., Moalli, F., Bianchessi, V., et al. (2019) · Nature · doi:10.1038/s41586-019-1620-6 · Cited by 222 · see citing works
Stem-like exhausted and memory CD8+ T cells in cancer
Gebhardt, T., Park, S. L., & Parish, I. A. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00615-0 · Cited by 216 · see citing works
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In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer
Chen, Z., Arai, E., Khan, O., Zhang, Z., Ngiow, S. F., He, Y. M., Huang, H., Manne, S., Cao, Z., Baxter, A. E., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.019 · Cited by 201 · see citing works
“These observations may be consistent with the observation that the Bcl-XL/Bim ratio may be more important in terminal TEFF survival than the Bcl-2/Bim ratio (Chen et al., 2017).”
Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor
Zhang, J., Li, J., Hou, Y., Lin, Y., Zhao, H., Shi, Y., Chen, K., Nian, C., Tang, J., Pan, L., et al. (2024) · Cell · doi:10.1016/j.cell.2024.04.023 · Cited by 213 · see citing works
Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis
Kaczanowska, S., Beury, D. W., Gopalan, V., Tycko, A. K., Qin, H., Clements, M. E., Drake, J. A., Nwanze, C., Murgai, M., Rae, Z., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.048 · Cited by 205 · see citing works
“5C) (Chen et al., 2019).”
Straathof, K. C. M., Flutter, B. R., Wallace, R., Jain, N., Loka, T., Depani, S., Wright, G., Thomas, S., Cheung, G. W.-K., Gileadi, T. E., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.abd6169 · Cited by 202 · see citing works
Nano-optogenetic engineering of CAR T cells for precision immunotherapy with enhanced safety
Nguyen, N. T., Huang, K., Zeng, H., Ji, J., Wang, R. Y., Fang, S., Chen, J., Liu, X., Huang, Z., You, M. J., et al. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00982-5 · Cited by 202 · see citing works
“To test this, we resorted to a mouse B16-OVA melanoma cell line stably expressing human CD19 (B16-OVA-hCD19) 15 and used the B16-OVA melanoma cells as the CD19-negative control (Supplementary Fig.”
Self-citationγδ T Cell Update: Adaptate Orchestrators of Immune Surveillance
Hayday, A. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1800934 · Cited by 199 · see citing works
“In this regard, Skint/Btnl-selected gd T cells are rich in Nr4a transcriptional regulators, which compose signatures of chronically activated CD8 TCRab tumor-infiltrating lymphocytes (82).”
BackgroundRavi, A., Hellmann, M. D., Arniella, M. B., Holton, M., Freeman, S. S., Naranbhai, V., Stewart, C., Leshchiner, I., Kim, J., Akiyama, Y., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01355-5 · Cited by 195 · see citing works
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“Strategies to eliminate the exhaustion-related gene programs downstream of NFAT activation in CAR-T cells have demonstrated enhanced antitumor activity (64).”
BackgroundWang, D., Prager, B. C., Gimple, R. C., Aguilar, B., Alizadeh, D., Tang, H., Lv, D., Starr, R., Brito, A., Wu, Q., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1243 · Cited by 185 · see citing works
From concept to cure: The evolution of CAR-T cell therapy
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CD3 bispecific antibody–induced cytokine release is dispensable for cytotoxic T cell activity
Li, J., Piskol, R., Ybarra, R., Chen, Y.-J. J., Li, J., Slaga, D., Hristopoulos, M. L., Clark, R., Modrusan, Z. D., Tótpál, K., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aax8861 · Cited by 180 · see citing works
“Cytokine secretion has also been proposed as a means to characterize the exhausted state of T cells (20, 21).”
BackgroundChen, Y., Zander, R., Wu, X., Schauder, D., Kasmani, M. Y., Shen, J., Zheng, S., Burns, R., Taparowsky, E. J., & Cui, W. (2021) · Nature Immunology · doi:10.1038/s41590-021-00965-7 · Cited by 177 · see citing works
Next-Generation CAR T-cell Therapies
Young, R. M., Engel, N. W., Uslu, U., Wellhausen, N., & June, C. H. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1683 · Cited by 182 · see citing works
Mechanisms of resistance to chimeric antigen receptor-T cells in haematological malignancies
Ruella, M., Korell, F., Porazzi, P., & Maus, M. V. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00807-1 · Cited by 182 · see citing works
Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer
Zhou, P., Shi, H., Huang, H., Sun, X., Yuan, S., Chapman, N. M., Connelly, J. P., Lim, S. A., Saravia, J., Anil, K. C., et al. (2023) · Nature · doi:10.1038/s41586-023-06733-x · Cited by 179 · see citing works
“The B16-hCD19 cell line was constructed by transducing B16-F10 cells with an amphotropic virus containing hCD19 and sorting cells with the top 10% of hCD19 expression 12 .”
BackgroundMethodInfluentialBile acid synthesis impedes tumor-specific T cell responses during liver cancer
Varanasi, S. K., Chen, D., Liu, Y., Johnson, M. A., Miller, C. M., Ganguly, S., Lande, K., LaPorta, M. A., Hoffmann, F. A., Mann, T. H., et al. (2025) · Science · doi:10.1126/science.adl4100 · Cited by 177 · see citing works
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Gene modification strategies for next-generation CAR T cells against solid cancers
Tian, Y., Li, Y., Shao, Y., & Zhang, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00890-6 · Cited by 177 · see citing works
Lu, Y.-J., Barreira‐Silva, P., Boyce, S., Powers, J., Cavallo, K., & Behar, S. M. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109696 · Cited by 172 · see citing works
Inosine induces stemness features in CAR-T cells and enhances potency
Klysz, D. D., Fowler, C., Malipatlolla, M. B., Stuani, L., Freitas, K. A., Chen, Y., Meier, S. L., Dániel, B., Sandor, K. D., Xu, P., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.01.002 · Cited by 178 · see citing works
Counteracting CAR T cell dysfunction
Poorebrahim, M., Melief, J., de Coaña, Y. P., Wickström, S. L., Arregui, A. C., & Kiessling, R. W. (2020) · Oncogene · doi:10.1038/s41388-020-01501-x · Cited by 169 · see citing works
Genetic engineering of T cells for immunotherapy
Ellis, G. I., Sheppard, N. C., & Riley, J. L. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00329-9 · Cited by 166 · see citing works
CD8+ T cell exhaustion and cancer immunotherapy
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“(encodes PD-1) expression as well as surface levels of PD-1 were significantly decreased in absence of NR4A and upregulated in NR4A-expressing cells (44).”
BackgroundKim, K.-S., Park, S., Park, S. Y., Kim, G., Park, S. M., Cho, J.-W., Kim, D., Park, Y. M., Koh, Y. W., Kim, H. R., et al. (2020) · Genome Medicine · doi:10.1186/s13073-020-00722-9 · Cited by 158 · see citing works
“The expression of NR4A1, a TF that induces T cell exhaustion [27, 28], was upregulated at later stages of the exhaustion state.”
BackgroundMechanisms of T-Cell Exhaustion in Pancreatic Cancer
Saka, D., Gökalp, M., Piyade, B., Çevik, N. C., Sever, E. A., Unutmaz, D., Ceyhan, G. O., Demir, İ. E., & Asimgil, H. (2020) · Cancers · doi:10.3390/cancers12082274 · Cited by 154 · see citing works
Enhanced T cell effector activity by targeting the Mediator kinase module
Freitas, K. A., Belk, J. A., Sotillo, E., Quinn, P. J., Ramello, M. C., Malipatlolla, M. B., Dániel, B., Sandor, K. D., Klysz, D. D., Bjelajac, J. R., et al. (2022) · Science · doi:10.1126/science.abn5647 · Cited by 155 · see citing works
“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…”
BackgroundInfluentialLiikanen, I., Lauhan, C. R., Quon, S., Omilusik, K. D., Phan, A. T., Bartrolí, L. B., Ferry, A., Goulding, J., Chen, J., Scott-Browne, J. P., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143729 · Cited by 152 · see citing works
“hCD19) as previously described (48) (Figure 9A and Supplemental Figure 6, A–D).”
BackgroundSelf-citationExhaustion of CAR T cells: potential causes and solutions
Kouro, T., Himuro, H., & Sasada, T. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03442-3 · Cited by 151 · see citing works
“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].”
BackgroundResultCheng, Y., Gunasegaran, B., Singh, H. D., Dutertre, C.-A., Loh, C. Y., Lim, J. Q., Crawford, J. C., Lee, H. K., Zhang, X., Lee, B., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.06.013 · Cited by 142 · see citing works
Self-citationRecent advances and applications of CRISPR-Cas9 in cancer immunotherapy
Liu, Z., Shi, M., Ren, Y., Xu, H., Weng, S., Ning, W., Ge, X., Liu, L., Guo, C., Duo, M., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01738-6 · Cited by 146 · see citing works
“The researches indicated that the deficiency of nuclear receptor 4A (NR4A) induced by Cre/LoxP, a site-specific knockout system mediated by Cre recombinases, leads to the down-regulation of PD1 and TIM-3 [79].”
BackgroundDeletion of Cbl-b inhibits CD8 + T-cell exhaustion and promotes CAR T-cell function
Kumar, J., Kumar, R., Singh, A. K., Tsakem, E. L., Kathania, M., Riese, M. J., Theiss, A. L., Davila, M. L., & Venuprasad, K. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001688 · Cited by 139 · see citing works
Lukhele, S., Abd-Rabbo, D., Guo, M., Shen, J., Elsaesser, H. J., Quevedo, R., Carew, M., Gadalla, R., Snell, L. M., Mahesh, L., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.020 · Cited by 135 · see citing works
Hossain, M. A., Liu, G., Dai, B., Si, Y., Yang, Q., Wazir, J., Birnbaumer, L., & Yang, Y. (2020) · Medicinal Research Reviews · doi:10.1002/med.21727 · Cited by 137 · see citing works
“NR4A deficiency in CD8+ CTLs displayed a strong en- richment in open chromatin regions with binding motifs for TFs involved in Teff functions, such as NF‐κB, basic region‐leucine zipper, T‐bet, and AP‐1.317 Interestingly, adoptive transfer of NR4A‐deficient chimeric antigen receptor T (CAR‐”
BackgroundInfluentialThe current state and future of T-cell exhaustion research
Jenkins, E. M., Whitehead, T., Fellermeyer, M., Davis, S. J., & Sharma, S. (2023) · Oxford Open Immunology · doi:10.1093/oxfimm/iqad006 · Cited by 136 · see citing works
“Summary of transcription factors expression associated with effector, progenitor and terminally exhausted T cells Transcription factor Effector T cell Progenitor exhausted T cell Terminally exhausted T cell References TCF-1 High High Low [8, 22] Ratio of T-bet and EOMES More T-bet More T-bet More EOMES [18, 19, 21] BA…”
BackgroundYoshikawa, T., Wu, Z., Inoue, S., Kasuya, H., Matsushita, H., Takahashi, Y., Kuroda, H., Hosoda, W., Suzuki, S., & Kagoya, Y. (2021) · Blood · doi:10.1182/blood.2021012714 · Cited by 131 · see citing works
Jung, I.-Y., Narayan, V., McDonald, S., Rech, A. J., Bartoszek, R. L., Hong, G., Suhoski, M. M., Xu, J., Boesteanu, A. C., Barber-Rotenberg, J. S., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abn7336 · Cited by 134 · see citing works
“We discovered that PRDM1 KO CAR T-cells chronically challenged with tumor targets display upregulation of a battery of exhaustion-associated transcription factors, including those belonging to the NR4A and TOX families which are reported to drive a cell-intrinsic program of T-cell hyporesponsiveness (50).”
BackgroundLecocq, Q., Keyaerts, M., Devoogdt, N., & Breckpot, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010075 · Cited by 135 · see citing works
Herring, J. A., Elison, W. S., & Tessem, J. S. (2019) · Cells · doi:10.3390/cells8111373 · Cited by 133 · see citing works
“H2O2 treatment is commonly used to measure cellular viability as ROS is sufficient to induce apoptosis [98,154,155].”
BackgroundT cell exhaustion in malignant gliomas
Watowich, M., Gilbert, M. R., & Larion, M. (2023) · Trends in cancer · doi:10.1016/j.trecan.2022.12.008 · Cited by 130 · see citing works
The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer
Safe, S. H., & Karki, K. (2020) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0707 · Cited by 130 · see citing works
“Analysis of tumor-infiltrating lymphocytes (TIL) shows that in exhausted T cells, NR4A is overexpressed, and this is accompanied by enhanced expression of PD-L1 and Tim3, decreased expression of cytokines, and low levels of cell killing (159).”
BackgroundPapavassiliou, A. G., & Musti, A. M. (2020) · Cells · doi:10.3390/cells9112470 · Cited by 122 · see citing works
“Furthermore, CAR T cells deficient in either TOX or NR4A reduced the expression of IRs and displayed greater chromatin accessibility at genomic regions enriched for motifs binding NF-κB and canonical AP-1 [29,31].”
BackgroundInfluentialAdvancing CAR T cell therapy through the use of multidimensional omics data
Yang, J., Chen, Y., Jing, Y., Green, M. R., & Han, L. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00729-2 · Cited by 128 · see citing works
- 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 › Neuroscience › Cellular and Molecular Neuroscience › 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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