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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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“Such un-sustained T-cell expansion associated with tumor relapse has been noted in previous studies in mice and humans, including prior studies on TCR-like CARs such as STAR and HIT (11, 13, 18, 52, 53, 65).”
InfluentialChen, Z., Zhu, Z., Hu, T., Yao, C., & Wu, T. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01378-4 · Cited by 37
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“In vivo mouse models discovered that over-expressing canonical AP-1 factor c-Jun in CAR-T cells enhanced CAR-T cell expansion, rendered resistance to T cell exhaustion, and augmented anti-tumour efficacy [45].”
BackgroundRegulatory T cell-based therapy in type 1 diabetes: Latest breakthroughs and evidence
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Kouakanou, L., Peters, C., Brown, C. E., Kabelitz, D., & Wang, L. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.765906 · Cited by 31
“Moreover, VitC may increase c-Jun levels (43) and Nuclear Factor of Activated T cell (NFAT) activity (86), and both c-Jun and NFAT have been shown to influence CAR T cell function (87).”
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Paixão, E. A., Barros, L. R. C., Fassoni, A. C., & Almeida, R. C. (2022) · Cancers · doi:10.3390/cancers14225576 · Cited by 30
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“When overexpressed, c-Jun led to increased CAR T cell expansion as well as enhanced functionality in murine solid tumor models [44].”
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“showed that the transcription factor c-Jun (part of the canonical AP-1 c-Fos–c-Jun heterodimer) plays a critical role in preventing adoptively transferred CAR-T cell exhaustion and that the efficacy of CAR-T cell therapy is significantly enhanced by c-Jun overexpression in several models [147].”
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Rapamycin enhances CAR-T control of HIV replication and reservoir elimination in vivo
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“Transcrip - tion factors, such as TOX [11], NR4A [12], and modulation of c-Jun expression [13], have been found to improve the resistance of CAR-T cells to exhaustion.”
T cell adaptation in chronic infections and tumors
Luxenburger, H., Thimme, R., & Hofmann, M. (2026) · Cellular and Molecular Immunology · doi:10.1038/s41423-026-01405-y · Cited by 20
“Moreover, overexpression of the AP-1 factor c-Jun is associated with resistance to exhaustion, suggesting that engineering “ next-generation ” CAR-T cells in a manner in which they overexpress c-Jun might be a promising approach to render them resistant to exhaustion-like chronic adaptation [215].”
Metabolic and epigenetic orchestration of (CAR) T cell fate and function
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“While targeted genetic ablation has the potential to disrupt pathways which restrain immune cell activation or contribute to exhaustion, knock-in of large gene cassettes, may hold even greater potential to reprogram immune cells for heightened effector functions or exhaustion resistance (32).”
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Challenges and optimal strategies of CAR T therapy for hematological malignancies
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How Can We Engineer CAR T Cells to Overcome Resistance?
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“expansion and improved anti-tumour responses against both solid tumour and leukemic xenograft models.(97)”
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“…modified a validated in vitro model of CAR-associated T cell exhaustion, wherein tonic CAR signaling induces hallmark phenotypic, functional, transcriptomic and epigenetic features of exhaustion within 11 days (HA.28ζ) (Lynn et al., 2019), to enable precise, drug-dependent control of CAR signaling.”
BackgroundMethodInfluentialSelf-citationIRF4 impedes human CD8 T cell function and promotes cell proliferation and PD-1 expression
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Resistance and recurrence of malignancies after CAR-T cell therapy
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Current studies and future promises of PD-1 signal inhibitors in cervical cancer therapy
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A synthetic biology approach to engineering circuits in immune cells
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“…are being explored in preclinical and clinical settings including a calibration of signaling strength through mutations in the CD3 ζ or CD28 domains, 74,75 gene knock-outs of key signaling transcription factors involved in exhaustion or overexpression of proteins such as c-Jun 71 or BATF.”
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A genetically encoded protein tag for control and quantitative imaging of CAR T cell therapy
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New targets and technologies for CAR-T cells
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Chimeric Antigen Receptor T Cell Exhaustion during Treatment for Hematological Malignancies
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“Engineering CAR-T cells to over-express c-Jun is an alternative approach to rendering CAR T cells resistant to exhaustion that has demonstrated pre-clinical promise (28).”
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Charging CAR by electrostatic power
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“4,52 Conversely, limited CAR signaling can result in suboptimal efficacy.”
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Small molecule-regulated switches to provide functional control of CAR T cells within the patient
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“Nevertheless, it is conceivable that this risk might increase with future generations of CAR T cells that are engineered for improved potency and persistence, e.g. by incorporating expression cassettes for (proto)oncogenes or transcription factors or by knocking out tumor suppressor genes [51,52].”
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RNA polymerase II pausing factor NELF in CD8+ T cells promotes antitumor immunity
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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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