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c-Jun overexpression in CAR T cells induces exhaustion resistance

Author

Listed:
  • Rachel C. Lynn

    (Stanford University School of Medicine
    Lyell Immunopharma)

  • Evan W. Weber

    (Stanford University School of Medicine)

  • Elena Sotillo

    (Stanford University School of Medicine)

  • David Gennert

    (Stanford University)

  • Peng Xu

    (Stanford University School of Medicine)

  • Zinaida Good

    (Stanford University School of Medicine
    Stanford University
    Parker Institute for Cancer Immunotherapy)

  • Hima Anbunathan

    (Stanford University School of Medicine)

  • John Lattin

    (Stanford University School of Medicine)

  • Robert Jones

    (Stanford University School of Medicine)

  • Victor Tieu

    (Stanford University School of Medicine)

  • Surya Nagaraja

    (Stanford University)

  • Jeffrey Granja

    (Stanford University)

  • Charles F. A. Bourcy

    (Stanford University
    Chan Zuckerberg Initiative)

  • Robbie Majzner

    (Stanford University School of Medicine)

  • Ansuman T. Satpathy

    (Stanford University
    Parker Institute for Cancer Immunotherapy)

  • Stephen R. Quake

    (Stanford University
    Chan Zuckerberg Biohub)

  • Michelle Monje

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine)

  • Howard Y. Chang

    (Stanford University
    Parker Institute for Cancer Immunotherapy
    Stanford University)

  • Crystal L. Mackall

    (Stanford University School of Medicine
    Parker Institute for Cancer Immunotherapy
    Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer1–3, but dysfunction due to T cell exhaustion is an important barrier to progress4–6. 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 cells7–10. 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.

Suggested Citation

  • Rachel C. Lynn & Evan W. Weber & Elena Sotillo & David Gennert & Peng Xu & Zinaida Good & Hima Anbunathan & John Lattin & Robert Jones & Victor Tieu & Surya Nagaraja & Jeffrey Granja & Charles F. A. B, 2019. "c-Jun overexpression in CAR T cells induces exhaustion resistance," Nature, Nature, vol. 576(7786), pages 293-300, December.
  • Handle: RePEc:nat:nature:v:576:y:2019:i:7786:d:10.1038_s41586-019-1805-z
    DOI: 10.1038/s41586-019-1805-z
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    Cited by:

    1. Justin A. Guerrero & Dorota D. Klysz & Yiyun Chen & Meena Malipatlolla & Jameel Lone & Carley Fowler & Lucille Stuani & Audre May & Malek Bashti & Peng Xu & Jing Huang & Basil Michael & Kévin Contrepo, 2024. "GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Carli M. Stewart & Elizabeth L. Siegler & R. Leo Sakemura & Michelle J. Cox & Truc Huynh & Brooke Kimball & Long Mai & Ismail Can & Claudia Manriquez Roman & Kun Yun & Olivia Sirpilla & James H. Girsc, 2024. "IL-4 drives exhaustion of CD8+ CART cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Veronika Bandara & Jade Foeng & Batjargal Gundsambuu & Todd S. Norton & Silvana Napoli & Dylan J. McPeake & Timona S. Tyllis & Elaheh Rohani-Rad & Caitlin Abbott & Stuart J. Mills & Lih Y. Tan & Emma , 2023. "Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Anneke L. Eerkens & Koen Brummel & Annegé Vledder & Sterre T. Paijens & Marta Requesens & Dominik Loiero & Nienke Rooij & Annechien Plat & Floris-Jan Haan & Patty Klok & Refika Yigit & Thijs Roelofsen, 2024. "Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Eishiro Mizukoshi & Hidetoshi Nakagawa & Toshikatsu Tamai & Masaaki Kitahara & Kazumi Fushimi & Kouki Nio & Takeshi Terashima & Noriho Iida & Kuniaki Arai & Tatsuya Yamashita & Taro Yamashita & Yoshio, 2022. "Peptide vaccine-treated, long-term surviving cancer patients harbor self-renewing tumor-specific CD8+ T cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    6. Xiaofeng Liao & Wenxue Li & Hongyue Zhou & Barani Kumar Rajendran & Ao Li & Jingjing Ren & Yi Luan & David A. Calderwood & Benjamin Turk & Wenwen Tang & Yansheng Liu & Dianqing Wu, 2024. "The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    7. Kwasi Adu-Berchie & Joshua M. Brockman & Yutong Liu & Tania W. To & David K. Y. Zhang & Alexander J. Najibi & Yoav Binenbaum & Alexander Stafford & Nikolaos Dimitrakakis & Miguel C. Sobral & Maxence O, 2023. "Adoptive T cell transfer and host antigen-presenting cell recruitment with cryogel scaffolds promotes long-term protection against solid tumors," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. Bogang Wu & Xiaowen Zhang & Huai-Chin Chiang & Haihui Pan & Bin Yuan & Payal Mitra & Leilei Qi & Hayk Simonyan & Colin N. Young & Eric Yvon & Yanfen Hu & Nu Zhang & Rong Li, 2022. "RNA polymerase II pausing factor NELF in CD8+ T cells promotes antitumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    9. Raymond Hall Yip Louie & Curtis Cai & Jerome Samir & Mandeep Singh & Ira W. Deveson & James M. Ferguson & Timothy G. Amos & Helen Marie McGuire & Kavitha Gowrishankar & Thiruni Adikari & Robert Balder, 2023. "CAR+ and CAR− T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. S. Fiorenza & Y. Zheng & J. Purushe & T. J. Bock & J. Sarthy & D. H. Janssens & A. S. Sheih & E. L. Kimble & D. Kirchmeier & T. D. Phi & J. Gauthier & A. V. Hirayama & S. R. Riddell & Q. Wu & R. Gotta, 2024. "Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Shiyu Zuo & Chuo Li & Xiaolei Sun & Biping Deng & Yibing Zhang & Yajing Han & Zhuojun Ling & Jinlong Xu & Jiajia Duan & Zelin Wang & Xinjian Yu & Qinlong Zheng & Xiuwen Xu & Jiao Zong & Zhenglong Tian, 2024. "C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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