Journal Article

c-Jun overexpression in CAR T cells induces exhaustion resistance

Xu, Peng, Nagaraja, Surya, Good, Zinaida, Tieu, Victor, Lattin, John, Quake, Stephen R., de Bourcy, Charles F. A., Sotillo, Elena, Monje, Michelle, Granja, Jeffrey, Satpathy, Ansuman T., Gennert, David, Mackall, Crystal L., Chang, Howard Y., Anbunathan, Hima, Jones, Robert, Majzner, Robbie, Weber, Evan W., Lynn, Rachel C.

2019

Overview

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 exhaustion 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 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/21 / 13/31 / 14/5 / 38 / 38/39 / 38/77 / 42/44 / 45/41 / 631/250/251 / 631/250/2520 / 64/60 / 82/80 / Activator protein 1 / Analysis / Animal models / Animals / Anticancer properties / Antigen receptors, T cell / Antigens / c-Jun N-terminal kinases / c-Jun protein / Cell Line, Tumor / Chemical compounds / Chimeric antigen receptors / Chromatin / Epigenesis, Genetic / Epigenetics / Exhaustion / Fatigue / Gene expression / Gene Expression Regulation / Humanities and Social Sciences / Humans / Hypotheses / Kinases / Lymphocytes / Lymphocytes T / Mice / multidisciplinary / Neoplasms - genetics / Neoplasms - immunology / Neoplasms - metabolism / Pharmacology / Prevention / Proto-Oncogene Proteins c-jun - genetics / Proto-Oncogene Proteins c-jun - metabolism / Receptors / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - immunology / Science / Science (multidisciplinary) / T cells / Transcription Factor AP-1 - genetics / Transcription Factor AP-1 - immunology / Transcription factors / Transcription, Genetic / Tumors