c-Jun overexpression in CAR T cells induces exhaustion resistance

Rachel C. Lynn, Evan W. Weber, Elena Sotillo, David Gennert, Peng Xu, Zinaida Good, Hima Anbunathan, John Lattin, Robert Jones, Victor Tieu, Surya Nagaraja, Jeffrey Granja, Charles F. A. Bourcy, Robbie Majzner, Ansuman T. Satpathy, Stephen R. Quake, Michelle Monje, Howard Y. Chang and Crystal L. Mackall ()
Additional contact information
Rachel C. Lynn: Stanford University School of Medicine
Evan W. Weber: Stanford University School of Medicine
Elena Sotillo: Stanford University School of Medicine
David Gennert: Stanford University
Peng Xu: Stanford University School of Medicine
Zinaida Good: Stanford University School of Medicine
Hima Anbunathan: Stanford University School of Medicine
John Lattin: Stanford University School of Medicine
Robert Jones: Stanford University School of Medicine
Victor Tieu: Stanford University School of Medicine
Surya Nagaraja: Stanford University
Jeffrey Granja: Stanford University
Charles F. A. Bourcy: Stanford University
Robbie Majzner: Stanford University School of Medicine
Ansuman T. Satpathy: Stanford University
Stephen R. Quake: Stanford University
Michelle Monje: Stanford University School of Medicine
Howard Y. Chang: Stanford University
Crystal L. Mackall: Stanford University School of Medicine

Nature, 2019, vol. 576, issue 7786, 293-300

Abstract: Abstract Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer1–3, but dysfunction due to T cell exhaustion is an important barrier to progress4–6. 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 exhaustion6. 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 cells7–10. 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (12)

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1805-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:576:y:2019:i:7786:d:10.1038_s41586-019-1805-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1805-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().