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NR4A transcription factors limit CAR T cell function in solid tumours

Author

Listed:
  • Joyce Chen

    (La Jolla Institute for Immunology
    University of California, San Diego
    University of California, San Diego
    Sanford Consortium for Regenerative Medicine)

  • Isaac F. López-Moyado

    (La Jolla Institute for Immunology
    Sanford Consortium for Regenerative Medicine
    University of California, San Diego)

  • Hyungseok Seo

    (La Jolla Institute for Immunology)

  • Chan-Wang J. Lio

    (La Jolla Institute for Immunology)

  • Laura J. Hempleman

    (La Jolla Institute for Immunology)

  • Takashi Sekiya

    (National Center for Global Health and Medicine)

  • Akihiko Yoshimura

    (Keio University School of Medicine)

  • James P. Scott-Browne

    (La Jolla Institute for Immunology
    Sanford Consortium for Regenerative Medicine
    National Jewish Health)

  • Anjana Rao

    (La Jolla Institute for Immunology
    University of California, San Diego
    Sanford Consortium for Regenerative Medicine
    University of California, San Diego)

Abstract

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies1,2. CAR T cells have been less effective against solid tumours3–5, in part because they enter a hyporesponsive (‘exhausted’ or ‘dysfunctional’) state6–9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19+ tumour-bearing mice. CD8+CAR+ tumour-infiltrating lymphocytes and CD8+ endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells)10–12. CD8+ T cells from humans with cancer or chronic viral infections13–15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8+ effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy.

Suggested Citation

  • Joyce Chen & Isaac F. López-Moyado & Hyungseok Seo & Chan-Wang J. Lio & Laura J. Hempleman & Takashi Sekiya & Akihiko Yoshimura & James P. Scott-Browne & Anjana Rao, 2019. "NR4A transcription factors limit CAR T cell function in solid tumours," Nature, Nature, vol. 567(7749), pages 530-534, March.
  • Handle: RePEc:nat:nature:v:567:y:2019:i:7749:d:10.1038_s41586-019-0985-x
    DOI: 10.1038/s41586-019-0985-x
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    Cited by:

    1. Alexandria C. Wells & Kaito A. Hioki & Constance C. Angelou & Adam C. Lynch & Xueting Liang & Daniel J. Ryan & Iris Thesmar & Saule Zhanybekova & Saulius Zuklys & Jacob Ullom & Agnes Cheong & Jesse Ma, 2023. "Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Marcel P. Trefny & Nicole Kirchhammer & Priska Auf der Maur & Marina Natoli & Dominic Schmid & Markus Germann & Laura Fernandez Rodriguez & Petra Herzig & Jonas Lötscher & Maryam Akrami & Jane C. Stin, 2023. "Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Haiyan Zhang & Xiaojing Luo & Wei Yang & Zhiying Wu & Zhicong Zhao & Xin Pei & Xue Zhang & Chonghao Chen & Josh Haipeng Lei & Qingxia Shi & Qi Zhao & Yanxing Chen & Wenwei Wu & Zhaolei Zeng & Huai-Qia, 2024. "YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. 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.
    5. Hao Wu & Xiufeng Zhao & Sophia M. Hochrein & Miriam Eckstein & Gabriela F. Gubert & Konrad Knöpper & Ana Maria Mansilla & Arman Öner & Remi Doucet-Ladevèze & Werner Schmitz & Bart Ghesquière & Sebasti, 2023. "Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-18, 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. Yi Liu & Brian Debo & Mingfeng Li & Zhennan Shi & Wanqiang Sheng & Yang Shi, 2021. "LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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