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c-Jun overexpression in CAR T cells induces exhaustion resistance
Open accessAbstract
Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer 1-3, but dysfunction due to T cell exhaustion is an important barrier to progress 4-6. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion 6. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells 7-10. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.
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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 [14]
In the citing paper
“Next-generation T cell therapies are being engineered with transgenes designed to overcome suppressive signals in the tumor environment (Kloss et al., 2018; Lynn et al., 2019; Yamamoto et al., 2019).”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Lynn et al., 2019
In the citing paper
“c-Jun overexpression protects CAR-T cells from dysfunction by inducing T-cell exhaustion resistance [157].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [157]
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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453
ggplot2: Elegant Graphics for Data Analysis
Wickham, H. (2009) · doi:10.1007/978-0-387-98141-3 · Cited by 14,447
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn923 · Cited by 14,108
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
Edgar, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.1.207 · Cited by 13,288
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174
NCBI GEO: archive for functional genomics data sets—update
Barrett, T., Wilhite, S. E., Ledoux, P., Evangelista, C., Kim, I. F., Tomashevsky, M., Marshall, K. A., Phillippy, K. H., Sherman, P. M., Holko, M., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1193 · Cited by 10,418
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
Massively parallel digital transcriptional profiling of single cells
Zheng, G. X. Y., Terry, J. M., Belgrader, P., Ryvkin, P., Bent, Z. W., Wilson, R., Ziraldo, S. B., Wheeler, T. D., McDermott, G. P., Zhu, J., et al. (2017) · Nature Communications · doi:10.1038/ncomms14049 · Cited by 7,353 · cited 1×
“The cell-gene matrix was further processed using the Cell Ranger R Kit software (10X Genomics) as described 57 .”
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“Strategies to achieve this goal include constructing logic-controlled CARs 127,131–134 , arming T cells with specific transgenes 135–139 and manipulating the genome 140–145 or epigenome 21,139,146 .”
Tieu, V., Sotillo, E., Bjelajac, J. R., Chen, C., Malipatlolla, M. B., Guerrero, J. A., Xu, P., Quinn, P. J., Fisher, C., Klysz, D. D., et al. (2024) · Cell · doi:10.1016/j.cell.2024.01.035 · Cited by 122
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BackgroundImproving CAR T-Cell Persistence
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BackgroundT-cell exhaustion in immune-mediated inflammatory diseases: New implications for immunotherapy
Gao, Z., Feng, Y., Xu, J., & Liang, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.977394 · Cited by 118
“C-Jun ∙ Downregulation/Functional deficiency in c-Jun mediates dysfunction in exhausted T-cells (33, 34)”
BackgroundTantalo, D. G. M., Oliver, A. J., von Scheidt, B., Harrison, A. J., Mueller, S. N., Kershaw, M. H., & Slaney, C. Y. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002555 · Cited by 112
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Nutrient-driven histone code determines exhausted CD8 + T cell fates
Ma, S., Dahabieh, M. S., Mann, T. H., Zhao, S., McDonald, B., Song, W., Chung, H., Farsakoglu, Y., Garcia-Rivera, L., Hoffmann, F. A., et al. (2024) · Science · doi:10.1126/science.adj3020 · Cited by 118
Self-citationReshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy
Xia, X., Yang, Z., Lu, Q., Liu, Z., Wang, L., Du, J., Li, Y., Yang, D., & Wu, S. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02079-8 · Cited by 112
GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency
Guerrero, J. A., Klysz, D. D., Chen, Y., Malipatlolla, M. B., Lone, J. B., Fowler, C., Stuani, L., May, A., Bashti, M., Xu, P., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52666-y · Cited by 120
“As we have previously shown 25,26 , the transcriptional programs of CD19.”
ResultSelf-citationLiu, L., Bi, E., Ma, X., Xiong, W., Qian, J., Ye, L., Pan, S., Wang, Q., Xiao, L., Yang, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19672-2 · Cited by 106
Zebley, C. C., Brown, C., Tian, M., Fan, Y., Alli, S., Boi, S. K., Galletti, G., Lugli, E., Langfitt, D. M., Métais, J., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110079 · Cited by 109
“tumors during chronic in vitro stimulation (Lynn et al., 2019).”
BackgroundCytokine-mediated CAR T therapy resistance in AML
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“We additionally derived an scRNA-seq-based exhaustion score from prior studies of T and CAR T cell exhaustion and applied these specifically to CART-123-expressing cells recovered from patient marrow aspirates collected at least 2 weeks after infusion 42,43 .”
The affinity of antigen-binding domain on the antitumor efficacy of CAR T cells: Moderate is better
Mao, R., Kong, W., & He, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1032403 · Cited by 110
“In addition, scientists have been studying strategies to improve CART fitness and persistence by selecting proper T cell subset (31), by reducing tonic signaling (such as utilizing 4-1BB (32) or single ITAM CD28 (33) as co-stimulatory domain), and by co-expressing CJun (34) or constitutive STAT5 (35).”
TCR Redirected T Cells for Cancer Treatment: Achievements, Hurdles, and Goals
Manfredi, F., Cianciotti, B. C., Potenza, A., Tassi, E., Noviello, M., Biondi, A., Ciceri, F., Bonini, C., & Ruggiero, E. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01689 · Cited by 108
“A deeper understanding of the expression profile associated to functional CAR-T cells has been now translated in new manipulation processes, involving the overexpression of transcription factors, such as c-Jun (391), or the deletion of inhibitory molecules such as REGNASE1 (392).”
BackgroundJUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models
Griffin, M., Borrelli, M. R., Garcia, J. T., Januszyk, M., King, M. E., Lerbs, T., Cui, L., Moore, A. L., Shen, A. H., Mascharak, S., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abb3312 · Cited by 105
Self-citationImproving the ability of CAR-T cells to hit solid tumors: Challenges and strategies
Zhang, Z., Wang, T., Wang, X.-F., Zhang, Y., Song, S., & Ma, C. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.106036 · Cited by 104
Cellular and molecular mechanisms of CD8(+) T cell differentiation, dysfunction and exhaustion
Verdon, D. J., Mulazzani, M., & Jenkins, M. R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197357 · Cited by 98
“[102] demonstrated that CAR constructs exhibiting continuous tonic signalling promoted exhaustion in CAR-T, resulting in loss of Figure 2.”
BackgroundFreimer, J. W., Shaked, O., Naqvi, S., Sinnott-Armstrong, N., Kathiria, A. S., Garrido, C. M., Chen, A. F., Cortez, J. T., Greenleaf, W. J., Pritchard, J. K., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01106-y · Cited by 99
CAR-T cells in solid tumors: Challenges and breakthroughs
Escobar, G., Berger, T. R., & Maus, M. V. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102353 · Cited by 114
“79 CAR-T cell fitness can also be improved by overexpressing transcriptional regulators such as JUN, 80 fork-head box O1 (FOXO1), 81,82 and basic leucine zipper ATF-like transcription factor (BATF).”
EpCAM-targeting CAR-T cell immunotherapy is safe and efficacious for epithelial tumors
Li, D., Guo, X., Yang, K., Yang, Y., Zhou, W., Huang, Y., Liang, X., Su, J., Jiang, L., Li, J., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg9721 · Cited by 97
“Also, c-Jun deficiency mediates CAR-T cell dysfunction, and engineering CAR-T cells to overexpress c-Jun endows CAR-T cells with exhaustion resistance ( 29 ).”
Mechanisms of CAR T cell exhaustion and current counteraction strategies
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In vitro modeling of CD8 + T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40
Wu, J. E., Manne, S., Ngiow, S. F., Baxter, A. E., Huang, H., Freilich, E., Clark, M. L., Lee, J. H., Chen, Z., Khan, O., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.ade3369 · Cited by 101
“Other models of in vitro Tex (8, 13, 14) may capture slightly different aspects of exhaustion.”
MethodCRISPR screens for functional interrogation of immunity
Shi, H., Doench, J. G., & Chi, H. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00802-4 · Cited by 102
“In solid tumours, ACT is often impeded by T cell dysfunction involving the upregulation of co-inhibitory receptors such as PD1 (refs.(71,165)).”
BackgroundNaturally occurring T cell mutations enhance engineered T cell therapies
Garcia, J. M., Daniels, J., Lee, Y., Zhu, I., Cheng, K., Liu, Q., Goodman, D. B., Burnett, C. E., Law, C., Thienpont, C., et al. (2024) · Nature · doi:10.1038/s41586-024-07018-7 · Cited by 97
Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus
Law, C., Wacleche, V. S., Cao, Y., Pillai, A., Sowerby, J. M., Hancock, B. L., Horisberger, A., Bracero, S., Skidanova, V., Li, Z., et al. (2024) · Nature · doi:10.1038/s41586-024-07627-2 · Cited by 104
Zhang, G., Gao, Z.-X., Guo, X., Ma, R., Wang, X., Zhou, P., Li, C., Tang, Z., Zhao, R., & Gao, P. (2023) · Journal of Clinical Investigation · doi:10.1172/jci166224 · Cited by 94
“JUN can cause the migration and infiltration of tumor cells, consistent with the function of CAP2 in GC cells (32, 33).”
ResultImpact of T cell characteristics on CAR-T cell therapy in hematological malignancies
Tao, Z., Chyra, Z., Kotulová, J., Celichowski, P., Mihályová, J., Charvátová, S., & Hájek, R. (2024) · Blood Cancer Journal · doi:10.1038/s41408-024-01193-6 · Cited by 101
“Some other engineering strategies have focused on restoring activator protein 1 (AP-1) function to prevent T-cell exhaustion by overexpressing the transcription factor c-Jun and the basic leucine zipper ATF-like transcription factor (BATF) [39, 40].”
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Diorio, C. J., Teachey, D. T., & Grupp, S. A. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-024-00959-y · Cited by 95
“For example, CAR T cells engineered to express the transcription factor JUN are less likely to become exhausted and have higher in vivo potency in mouse models 17 .”
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Liu, Y., An, L., Huang, R., Xiong, J., Yang, H., Wang, X., & Zhang, X. (2022) · Biomarker Research · doi:10.1186/s40364-022-00434-9 · Cited by 97
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BackgroundZheng, W., Wei, J., Zebley, C. C., Jones, L. L., Dhungana, Y., Wang, Y., Mavuluri, J., Long, L., Fan, Y., Youngblood, B., et al. (2021) · Blood · doi:10.1182/blood.2020009309 · Cited by 89
Jackson, Z., Hong, C., Schauner, R., Dropulić, B., Caimi, P. F., Lima, M. J. G. D., Giraudo, M. F., Gupta, K., Reese, J., Hwang, T. H., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1586 · Cited by 85
Li, X., Li, Y., Dong, L., Chang, Y., Zhang, X., Wang, C., Chen, M., Bo, X., Chen, H., Han, W., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci165673 · Cited by 92
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Escobar, G., Tooley, K., Oliveras, J. P., Huang, L., Cheng, H., Bookstaver, M. L., Edwards, C., Froimchuk, E., Xue, C., Mangani, D., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.08.001 · Cited by 91
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Ma, C., Zheng, K., Jiang, K., Zhao, Q., Sha, N., Wang, W., Yan, M., Chen, T., Zhao, Y., & Jiang, Y. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00456-x · Cited by 89
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Simonetta, F., Alam, I. S., Lohmeyer, J. K., Sahaf, B., Good, Z., Chen, W., Xiao, Z., Hirai, T., Scheller, L., Engels, P., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2770 · Cited by 84
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“…such as NR4A1, DNMT3A, SMARCA4 and SMARCA2, through gene perturbation, protein degraders or inhibitors to boost CAR T cell efficacy 317,321,322 , while overexpressing key exhaustion inhibitors, such as AP-1 family members like c-Jun, BATF or BATF3, offers another promising strategy 323–325 .”
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Cox, M. J., Lucien, F., Sakemura, R. L., Boysen, J. C., Kim, Y., Horvei, P., Roman, C. M., Hansen, M. J., Tapper, E. E., Siegler, E. L., et al. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.12.033 · Cited by 85
Zhu, M., Han, Y., Gu, T., Wang, R. Y., Si, X., Kong, D., Zhao, P., Wang, X., Li, J., Zhai, X., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114065 · Cited by 90
Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade
Palmer, D. C., Webber, B. R., Patel, Y. K., Johnson, M. J., Kariya, C. M., Lahr, W. S., Parkhurst, M. R., Gartner, J. J., Prickett, T. D., Lowery, F. J., et al. (2022) · Med · doi:10.1016/j.medj.2022.07.008 · Cited by 82
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Lamarche, C., Ward‐Hartstonge, K. A., Tian, M., Lin, D. T. S., Huang, Q. B., Brown, A., Edwards, K., Novakovsky, G., Qi, C. N., Kobor, M. S., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2219086120 · Cited by 87
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Humanized Mice Are Precious Tools for Preclinical Evaluation of CAR T and CAR NK Cell Therapies
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“[148] investigated this important issue using a tonically signaling CAR, driving healthy CAR T cells to exhaustion [12].”
BackgroundKhan, S. H., Choi, Y., Veena, M. S., Lee, J. K., & Shin, D. S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1489827 · Cited by 84
“In the context of engineering CAR T cells, the overexpression of canonical AP-1 factor c-Jun has enhanced T cell expansion potential, increased functional capacity, and improved anti-tumor response in multiple in vivo mouse tumor models (205).”
Granhøj, J. S., Jensen, A. W. P., Presti, M., Met, Ö., Svane, I. M., & Donia, M. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2064711 · Cited by 76
“sion of specific receptors [172] or transcription factors [173] could be of interest.”
BackgroundPatrick, R., Naval-Sánchez, M., Deshpande, N., Huang, Y., Zhang, J., Chen, X., Yang, Y., Tiwari, K., Esmaeili, M., Tran, M., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.06.006 · Cited by 76
SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors
López-Cobo, S., Fuentealba, J. R., Gueguen, P., Bonté, P.-E., Tsalkitzi, K., Chacón, I., Glauzy, S., Bohineust, A., Biquand, A., Silva, L., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1350 · Cited by 72
A multi-omics approach to reveal critical mechanisms of activator protein 1 (AP-1)
Li, F., Tian, J., Zhang, L., He, H., & Song, D. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117225 · Cited by 72
Perspective for Precision Medicine for Tuberculosis
Lange, C. G., Aarnoutse, R. E., Chesov, D., van Crevel, R., Gillespie, S. H., Grobbel, H.-P., Kalsdorf, B., Kontsevaya, I., van Laarhoven, A., Nishiguchi, T., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.566608 · Cited by 70
Jung, I.-Y., Noguera-Ortega, E., Bartoszek, R. L., Collins, S. M., Williams, E. F., Suhoski, M. M., Jadlowsky, J. K., Plesa, G., Siegel, D. L., Chew, A., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101053 · Cited by 74
Dynamic chromatin regulatory landscape of human CAR T cell exhaustion
Gennert, D. G., Lynn, R. C., Granja, J. M., Weber, E. W., Mumbach, M. R., Zhao, Y., Duren, Z., Sotillo, E., Greenleaf, W. J., Wong, W. H., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2104758118 · Cited by 70
Self-citationModular pooled discovery of synthetic knockin sequences to program durable cell therapies
Blaeschke, F., Chen, Y. Y., Apathy, R., Dániel, B., Chen, A. Y., Chen, P. A., Sándor, K., Zhang, W., Li, Z., Mowery, C. T., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.013 · Cited by 71
Self-citationAP-1 transcription factors in cytotoxic lymphocyte development and antitumor immunity
Schnoegl, D., Hiesinger, A., Huntington, N. D., & Gotthardt, D. (2023) · Current Opinion in Immunology · doi:10.1016/j.coi.2023.102397 · Cited by 70
Exhausted T cells and epigenetic status
Zeng, Z., Wei, F., & Ren, X. (2020) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2020.0338 · Cited by 73
A Chimeric GM-CSF/IL18 Receptor to Sustain CAR T-cell Function
Lange, S., Sand, L. G. L., Bell, M., Patil, S. L., Langfitt, D., & Gottschalk, S. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0896 · Cited by 68
“Several approaches are being developed to improve the antitumor activity of CAR T-cells including the expression of transcription factors, cytokines, constitutively active cytokine receptors, inducible costimulatory molecules, or chimeric cytokine or switch receptors (10-12).”
BackgroundNon-viral chimeric antigen receptor (CAR) T cells going viral
Balke‐Want, H., Keerthi, V., Cadiñanos-Garai, A., Fowler, C., Gkitsas-Long, N., Brown, A. K., Tunuguntla, R. H., Abou‐El‐Enein, M., & Feldman, S. A. (2023) · Immuno-Oncology Technology · doi:10.1016/j.iotech.2023.100375 · Cited by 75
Shao, M., Teng, X., Guo, X., Zhang, H., Huang, Y., Cui, J., Si, X., Ding, L., Wang, X., Li, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202103508 · Cited by 67
Singh, S., Lee, N., Pedroza, D. A., Bado, I., Hamor, C., Zhang, L., Aguirre, S., Hu, J., Shen, Y., Xu, Y., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-3714 · Cited by 64
Li, X., Guo, X., Zhu, Y., Wei, G., Zhang, Y., Li, X., Xu, H., Cui, J., Wu, W., He, J., et al. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.11.028 · Cited by 70
Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models
Si, X., Xiao, L., Brown, C. E., & Wang, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063154 · Cited by 70
“Refinement of CAR constructs [105–111] Memory of CAR T cells [42,63,112] CAR T cell trafficking [113–115] Adverse effects and CRS [109,116,120]”
BackgroundImmunotherapy in Pancreatic Adenocarcinoma: Beyond “Copy/Paste”
Hester, R., Mazur, P. K., & McAllister, F. M. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0900 · Cited by 67
“Enforced expression of those transcription factors alongside CAR can prevent an exhaustion phenotype (108, 109).”
BackgroundMechanisms of T cell exhaustion guiding next-generation immunotherapy
Zebley, C. C., & Youngblood, B. (2022) · Trends in Cancer · doi:10.1016/j.trecan.2022.04.004 · Cited by 65
BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia
Zhong, M., Gao, R., Zhao, R., Huang, Y., Chen, C., Li, K., Yu, X., Nie, D., Chen, Z., Liu, X., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05123-x · Cited by 64
“5M), which has been reported to rescue exhaustion in HA-28z CAR T cells [41].”
BackgroundAhn, T., Bae, E., & Seo, H. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.04.004 · Cited by 71
“Furthermore, innovative approaches, such as overexpressing c-Jun, which is part of the AP-1 transcriptional family, have shown promising results in improving the functional and proliferative capacities and in vivo antitumor activities of modi fi ed T cells 94 (Figure 3).”
Roex, G., Feys, T., Beguin, Y. P., Kerre, T. C. C., Poiré, X., Lewalle, P., Vandenberghe, P., Bron, D., & Anguille, S. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12020194 · Cited by 65
“Alternatively, CAR-T cells can also be “armored” with c-Jun to prevent their exhaustion [71].”
BackgroundMechanisms of immune effector cell‐associated neurotoxicity syndrome after CAR‐T treatment
Gu, T., Hu, K., Si, X., Hu, Y., & Huang, H. (2022) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1576 · Cited by 69
Mueller, K. P., Piscopo, N. J., Forsberg, M. H., Saraspe, L. A., Das, A., Russell, B., Smerchansky, M. E., Cappabianca, D., Shi, L., Shankar, K., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004446 · Cited by 62
Burton, J., Siller‐Farfán, J. A., Pettmann, J., Salzer, B., Kutuzov, M. A., van der Merwe, P. A., & Dushek, O. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2216352120 · Cited by 63
Proteotoxic stress response drives T cell exhaustion and immune evasion
Wang, Y., Ma, A., Song, N.-J., Shannon, A. E., Amankwah, Y. S., Chen, X., Wu, W., Wang, Z., Saadey, A. A., Yousif, A., et al. (2025) · Nature · doi:10.1038/s41586-025-09539-1 · Cited by 68
Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML
Nixdorf, D., Sponheimer, M., Berghammer, D., Engert, F., Bader, U., Philipp, N., Pasikhani, M. K., Straub, T., Rohrbacher, L., Wange, L. E., et al. (2023) · Leukemia · doi:10.1038/s41375-023-01905-0 · Cited by 63
“Another cause of CAR T-cell failure is T-cell dysfunction, the reasons for which are multifaceted, ranging from the quality of the T cells at the time of apheresis [8, 9], remodeling by the tumor microenvironment [10–14], chronic antigen exposure [15, 16], also caused by the intrinsic resistance of AML cells due to im…”
BackgroundCostimulatory domains direct distinct fates of CAR-driven T cell dysfunction
Selli, M. E., Landmann, J. H., Terekhova, M., Lattin, J., Heard, A. D., Hsu, Y.-S., Chang, T.-C., Chang, J., Warrington, J. M., Ha, H., et al. (2023) · Blood · doi:10.1182/blood.2023020100 · Cited by 63
Self-citationTargets of tumor microenvironment for potential drug development
Zhang, L., Wang, Z., Liu, K., Liu, Y., Wang, S., Jiang, W., Lu, F., & Dang, Y. (2024) · MedComm – Oncology · doi:10.1002/mog2.68 · Cited by 68
“48,49 To counteract this, several novel approaches have been proposed, such as overexpression of c ‐ JUN, 50 deletion of nuclear receptor subfamily 4A (NR4A), 51 and transient induction of resting T cells by dasatinib.”
Prospects and challenges for use of CAR T cell therapies in solid tumors
Ramakrishna, S., Barsan, V. V., & Mackall, C. L. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1738378 · Cited by 62
Self-citationRust, B. J., Kean, L. S., Colonna, L., Brandenstein, K. E., Poole, N. H., Obenza, W., Enstrom, M. R., Maldini, C. R., Ellis, G. I., Fennessey, C. M., et al. (2020) · Blood · doi:10.1182/blood.2020006372 · Cited by 58
RetractedTo go or not to go? Biological logic gating engineered T cells
Abbott, R. C., Hughes‐Parry, H. E., & Jenkins, M. R. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004185 · Cited by 61
“54 55 Some early evidence has been published suggesting that logic-gating T cells can influence T cell fitness.”
BackgroundWilson, T. L., Kim, H., Chou, C., Langfitt, D. M., Mettelman, R. C., Minervina, A. A., Allen, E. K., Métais, J., Pogorelyy, M. V., Riberdy, J. M., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1508 · Cited by 58
Adu‐Berchie, K., Brockman, J. M., Liu, Y., To, T., Zhang, D. K. Y., Najibi, A. J., Binenbaum, Y., Stafford, A. G., Dimitrakakis, N., Sobral, M. C., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39330-7 · Cited by 60
“Previous studies have shown that approaches that promote resistance of CAR T cells to exhaustion 32 or directly boost their expansion in vivo 33 can lead to better therapeutic responses to solid tumors.”
Frontiers in cancer immunotherapy—a symposium report
Cable, J., Greenbaum, B. D., Pe’er, D., Bollard, C. M., Bruni, S., Griffin, M. E., Allison, J. P., Wu, C. J., Subudhi, S. K., Mardis, E. R., et al. (2020) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14526 · Cited by 65
Self-citationAntigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance
Wagle, M. V., Vervoort, S. J., Kelly, M. J., Byl, W. V. D., Peters, T. J., Martin, B. P., Martelotto, L. G., Nüssing, S., Ramsbottom, K. M., Torpy, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23044-9 · Cited by 62
Engineering chimeric antigen receptor T cells for solid tumour therapy
Liu, L., Qu, Y., Cheng, L., Yoon, C. W., He, P., Monther, A., Guo, T., Chittle, S. J., & Wang, Y. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.1141 · Cited by 61
Zhou, Z., Wang, J., Wang, J., Yang, S., Wang, R., Zhang, G., Li, Z., Shi, R., Wang, Z., & Lu, Q. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02047-2 · Cited by 66
“Engineering CAR-T cells to overexpress c-Jun (a typical AP-1 factor) increased CAR-T expansion, enhanced effector function, and reduced differentiation towards terminal exhaustion, resulting in a more potent anti-tumor effect [174].”
BackgroundXu, X., Huang, S., Xiao, X., Sun, Q., Liang, X., Chen, S., Zhao, Z., Huo, Z., Tu, S., & Li, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.569117 · Cited by 62
“Moreover, c-Jun overexpression (123) and the immune-suppressive bone marrow microenvironment (124) are likely to be parameters related to antigen-positive relapse in CAR T-cell therapy.”
BackgroundWang, J., Xie, S.-A., Li, N., Zhang, T., Yao, W., Zhao, H., Pang, W., Han, L., Liu, J., & Zhou, J. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.01.012 · Cited by 59
Emerging CAR T Cell Strategies for the Treatment of AML
Vishwasrao, P., Li, G., Boucher, J. C., Smith, D. L., & Hui, S. K. (2022) · Cancers · doi:10.3390/cancers14051241 · Cited by 61
Metadata
- Authors
- Lynn, R. C., Weber, E. W., Sotillo, E., Gennert, D., Xu, P., Good, Z., Anbunathan, H., Lattin, J., Jones, R., Tieu, V., Nagaraja, S., Granja, J., de Bourcy, C. F. A., Majzner, R., Satpathy, A. T., Quake, S. R., Monje, M., Chang, H. Y., & Mackall, C. L.
- Affiliations
- Lyell Immunopharma (United States) (US)
- Stanford Medicine (US)
- Stanford University (US)
- Parker Institute for Cancer Immunotherapy (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mackall, Crystal L.
- ORCID
- Venue
- Nature
- Published
- 2019-12-04
- Volume
- 576
- Issue
- 7786
- Pages
- 293-300
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6944329
- OpenAlex
- W2992738455
- Cited by
- 891
- References
- 63
- Citations by year
- 2026: 141 · 2025: 151 · 2024: 138 · 2023: 129 · 2022: 122 · 2021: 119 · 2020: 89 · 2019: 1
- FWCI
- 34.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10od018220-01)
- National Human Genome Research Institute (RM1HG007735, P50HG007735)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- c-Jun, chimeric antigen receptor T cells, T cell exhaustion, AP-1 transcription factor, IL-2 deficiency, chromatin accessibility, IRF transcription factors, bZIP transcription factors, T cell expansion, antitumor immunity, CAR-T cell engineering
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Neoplasms, Receptors, Antigen, T-Cell, Transcription, Genetic, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, Epigenesis, Genetic, Cell Line, Tumor, Mice
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