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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
Nature, 12/2019, Volume: 576, Issue: 7786Journal Article
Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer , but dysfunction due to T cell exhaustion is an important barrier to progress . 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 . 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 . 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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