NR4A transcription factors limit CAR T cell function in solid tumours

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

Research output: Contribution to journalLetter

12 Citations (Scopus)

Abstract

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies 1,2 . CAR T cells have been less effective against solid tumours 3–5 , in part because they enter a hyporesponsive (‘exhausted’ or ‘dysfunctional’) state 6–9 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 infections 13–15 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.

Original languageEnglish
Pages (from-to)530-534
Number of pages5
JournalNature
Volume567
Issue number7749
DOIs
Publication statusPublished - 2019 Mar 28

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Transcription Factors
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Neoplasms
Chromatin
Transcriptome
Programmed Cell Death 1 Receptor
NFATC Transcription Factors
Transcription Factor AP-1
Virus Diseases
Cytoplasmic and Nuclear Receptors
T-Cell Antigen Receptor
Immunotherapy
B-Lymphocytes
Up-Regulation
Phenotype
Antigens

ASJC Scopus subject areas

  • General

Cite this

Chen, J., López-Moyado, I. F., Seo, H., Lio, C. W. J., Hempleman, L. J., Sekiya, T., ... Rao, A. (2019). NR4A transcription factors limit CAR T cell function in solid tumours. Nature, 567(7749), 530-534. https://doi.org/10.1038/s41586-019-0985-x

NR4A transcription factors limit CAR T cell function in solid tumours. / Chen, Joyce; López-Moyado, Isaac F.; Seo, Hyungseok; Lio, Chan Wang J.; Hempleman, Laura J.; Sekiya, Takashi; Yoshimura, Akihiko; Scott-Browne, James P.; Rao, Anjana.

In: Nature, Vol. 567, No. 7749, 28.03.2019, p. 530-534.

Research output: Contribution to journalLetter

Chen, J, López-Moyado, IF, Seo, H, Lio, CWJ, Hempleman, LJ, Sekiya, T, Yoshimura, A, Scott-Browne, JP & Rao, A 2019, 'NR4A transcription factors limit CAR T cell function in solid tumours', Nature, vol. 567, no. 7749, pp. 530-534. https://doi.org/10.1038/s41586-019-0985-x
Chen J, López-Moyado IF, Seo H, Lio CWJ, Hempleman LJ, Sekiya T et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019 Mar 28;567(7749):530-534. https://doi.org/10.1038/s41586-019-0985-x
Chen, Joyce ; López-Moyado, Isaac F. ; Seo, Hyungseok ; Lio, Chan Wang J. ; Hempleman, Laura J. ; Sekiya, Takashi ; Yoshimura, Akihiko ; Scott-Browne, James P. ; Rao, Anjana. / NR4A transcription factors limit CAR T cell function in solid tumours. In: Nature. 2019 ; Vol. 567, No. 7749. pp. 530-534.
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abstract = "T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies 1,2 . CAR T cells have been less effective against solid tumours 3–5 , in part because they enter a hyporesponsive (‘exhausted’ or ‘dysfunctional’) state 6–9 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 infections 13–15 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.",
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AU - Hempleman, Laura J.

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