biostudies-literatureLynn RCHoward Hughes Medical InstituteNHGRI NIH HHSNIH HHS293-300https://www.ebi.ac.uk/biostudies/studies/S-EPMC6944329biostudies-literatureUnknown576(7786)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 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 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.Naturec-Jun overexpression in CAR T cells induces exhaustion resistance.PMC6944329P50 HG007735S10 OD018220RM1 HG007735Majzner RXu PAnbunathan HGranja JChang HYWeber EWGood ZLynn RCNagaraja Sde Bourcy CFASotillo EGennert DTieu VQuake SRMackall CLSatpathy ATJones RMonje MLattin Jfalsec-Jun overexpression in CAR T cells induces exhaustion resistance.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 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 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.2019-01-01T00:00:00Z2019 Dec2024-11-15T22:55:19.206Z2020-06-07T07:02:03ZS-EPMC69443293180200410.1038/s41586-019-1805-z