c-Jun overexpression in CAR T cells induces exhaustion resistance

SUMMARY

CAR T cells mediate antitumor effects in a small subset of cancer patients ^{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 employing a tonically signaling CAR, which induces hallmark features of exhaustion ⁶ . Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of bZIP and IRF transcription factors that have been implicated in mediating the dysfunctional program present in exhausted cells ^{7– 10} . Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in five different in vivo tumor models. 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 exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.