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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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“To better understand the mechanisms leading to exhaustion, Lynn et al. 59 recently developed a cellular model of exhaustion by introducing a tonic signalling CAR (HA-28z CAR) into T cells.”
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“These cells showed different chromatin accessibility, enhanced expansion and functional capacity, and improved anti-tumor activity in five different tumor mouse models in vivo (189).”
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BackgroundTET2 guards against unchecked BATF3-induced CAR T cell expansion
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“c-Jun overexpression can exhibit CAR-T cell exhaustion resistance, improve expansion potential, reduce terminal differentiation, and improve its anti-tumor potency in in vivo models (103).”
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Co-Stimulatory Receptor Signaling in CAR-T Cells
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“…ATAC-seq also demonstrated limited differences in the open chromatin (Figures 2F and S4), but showed enrichment in good expander CAR-T products of AP-1 factor transcription factor (TF) motifs, such as BATF, JUN, and FOS, signals previously implicated in exhaustion-resistant T cells 29 (Figure 2G).”
BackgroundSelf-citation
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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