Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
 

Learn about the flu shot, COVID-19 vaccine, and our masking policy »

Stanford Health Care

c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature Lynn, R. C., Weber, E. W., Sotillo, E. n., Gennert, D. n., Xu, P. n., Good, Z. n., Anbunathan, H. n., Lattin, J. n., Jones, R. n., Tieu, V. n., Nagaraja, S. n., Granja, J. n., de Bourcy, C. F., Majzner, R. n., Satpathy, A. T., Quake, S. R., Monje, M. n., Chang, H. Y., Mackall, C. L. 2019

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.

View details for DOI 10.1038/s41586-019-1805-z

View details for PubMedID 31802004