Cited by 897CAR-T cell therapy researchT-cell and B-cell ImmunologyCancer Immunotherapy and Biomarkers

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c-Jun overexpression in CAR T cells induces exhaustion resistance

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Lynn, Rachel C., Weber, Evan W., Sotillo, Elena, Gennert, David, Xu, Peng, Good, Zinaida, Anbunathan, Hima, Lattin, John, Jones, Robert, Tieu, Victor, Nagaraja, Surya, Granja, Jeffrey, de Bourcy, Charles F. A., Majzner, Robbie, Satpathy, Ansuman T., Quake, Stephen R., Monje, Michelle, Chang, Howard Y., Mackall, Crystal L.·2019·Nature

DOI 10.1038/s41586-019-1805-zPMC PMC6944329

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Abstract

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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“Second, a prior work has shown that c-Jun overexpression can mitigate CAR-T cell exhaustion 45 .”

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: Lynn, Rachel C.
Weber, Evan W.
Sotillo, Elena
Gennert, David
Xu, Peng
Good, Zinaida
Anbunathan, Hima
Lattin, John
Jones, Robert
Tieu, Victor
Nagaraja, Surya
Granja, Jeffrey
Majzner, Robbie
Satpathy, Ansuman T.
Quake, Stephen R.
Monje, Michelle
Chang, Howard Y.
Mackall, Crystal L.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-12-04
Volume: 576
Issue: 7786
Pages: 293-300
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-1805-z
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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c-Jun overexpression in CAR T cells induces exhaustion resistance

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