c-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.sup.1-3, but dysfunction due to T cell exhaustion is an important barrier to progress.sup.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.sup.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.sup.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. Chimeric antigen receptor (CAR) T cells engineered to overexpress the canonical AP-1 transcription factor c-Jun are resistant to T cell exhaustion, and provide enhanced therapeutic benefit in mouse tumour models.
Author(s): Rachel C. Lynn [sup.1] [sup.11] , Evan W. Weber [sup.1] , Elena Sotillo [sup.1] , David Gennert [sup.2] , Peng Xu [sup.1] , Zinaida Good [sup.1] [sup.3] [sup.4] , [...]