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NR4A transcription factors limit CAR T cell function in solid tumours
- Source :
- Signal Transduction and Targeted Therapy
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
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. Transfer of NR4A-deficient T cells expressing chimeric antigen receptors is shown to reduce tumour burden and increase survival by shifting T cell transcriptional programs away from exhaustion and towards increased effector function.
- Subjects :
- Male
0301 basic medicine
Receptors, Steroid
Adoptive cell transfer
T cell
Antigens, CD19
Melanoma, Experimental
CD8-Positive T-Lymphocytes
CD19
Mice
03 medical and health sciences
Lymphocytes, Tumor-Infiltrating
0302 clinical medicine
Antigen
Cell Line, Tumor
Neoplasms
Nuclear Receptor Subfamily 4, Group A, Member 2
Nuclear Receptor Subfamily 4, Group A, Member 1
medicine
Animals
Humans
Transcription factor
B cell
Research Highlight - Invited
Receptors, Chimeric Antigen
Receptors, Thyroid Hormone
Multidisciplinary
biology
Chemistry
Gene Expression Profiling
NF-kappa B
Adoptive Transfer
Chromatin
Chimeric antigen receptor
3. Good health
Cell biology
DNA-Binding Proteins
Mice, Inbred C57BL
Survival Rate
Transcription Factor AP-1
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
biology.protein
Female
CD8
Transcription Factors
Subjects
Details
- ISSN :
- 14764687 and 00280836
- Volume :
- 567
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....6b67002124b96fce99169d119f849a3f