NR4A transcription factors limit CAR T cell function in solid tumours

Chen, Joyce; López-Moyado, Isaac F.; Seo, Hyungseok; Lio, Chan-Wang Jerry; Hempleman, Laura J.; Sekiya, Takashi; Yoshimura, Akihiko; Scott‐Browne, James; Rao, Anjana

doi:10.1038/s41586-019-0985-x

Cited by 617 publications

(602 citation statements)

References 46 publications

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“…However, higher expression levels of inhibitory receptors observed in the GFP hi population were not unique to SKGNur T cells since WTNur GFP hi CD4 T cells also upregulated inhibitory receptors compared to WTNur GFP lo CD4 T cells. This is in line with a recent report demonstrating that NR4A gene expression positively correlated with PDCD1 (PD-1), TIGIT, and other inhibitory receptors in the setting of chronic antigen stimulation as part of a T cell-intrinsic program of hyporesponsiveness (40). This may in part account for the relative hyporesponsiveness we observed in GFP hi T cells ( Fig.…”

Section: Upregulation Of Several Inhibitory Receptors In Skg Gfp Hi Csupporting

confidence: 93%

Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis

Ashouri

Hsu

et al. 2018

Preprint

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How pathogenic CD4 T cells in Rheumatoid Arthritis (RA) develop remains poorly understood.We used Nur77-a marker of T cell antigen receptor (TCR) signaling-to identify antigenactivated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA.Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into IL-17 producing cells. The T cells with increased autoreactivity, nonetheless had diminished ex vivo inducible TCR signaling, perhaps reflective of adaptive inhibitory mechanisms induced by chronic auto-antigen exposure in vivo. The enhanced autoreactivity was associated with upregulation of IL-6 cytokine signaling machinery, which might in part be attributable to a reduced amount of expression of suppressor of cytokine signaling 3 (SOCS3)-a key negative regulator of IL-6 signaling. As a result, the more autoreactive GFP hi CD4 T cells from SKGNur mice were hyper-responsive to IL-6 receptor signaling. Consistent with findings from SKGNur mice, SOCS3 expression was similarly downregulated in RA synovium. This suggests that, despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6 which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA.

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Section: Upregulation Of Several Inhibitory Receptors In Skg Gfp Hi Csupporting

confidence: 93%

Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis

Ashouri

Hsu

et al. 2018

Preprint

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“…Recent studies have identified TOX, TOX2, and AP-1 family members as central regulators of human T cell exhaustion that promote widespread transcriptional and epigenetic dysregulation (Alfei et al, 2019;Khan et al, 2019;Scott et al, 2019;Seo et al, 2019;Wang et al, 2019;Yao et al, 2019). These findings have enabled new approaches to mitigate exhaustion, including enforced expression of c-Jun or CRISPR-mediated deletion of TOX, TOX2, or NR4A family TFs (Chen et al, 2019a;Seo et al, 2019). However, such modifications do not result in wholescale remodeling of the exhaustion-associated epigenome, suggesting that exhaustion is an epigenetically fixed cell state.…”

Section: Discussionmentioning

confidence: 99%

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Weber

Lynn

Parker

et al. 2020

Preprint

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T cell exhaustion limits immune responses against cancer and is a major cause of resistance to CAR-T cell therapeutics. Using a model wherein tonic CAR signaling induces hallmark features of exhaustion, we employed a drug-regulatable CAR to test the impact of transient cessation of receptor signaling (i.e. "rest") on the development and maintenance of exhaustion. Induction of rest in exhausting or already-exhausted CAR-T cells resulted in acquisition of a memory-like phenotype, improved antitumor functionality, and wholescale transcriptional and epigenetic reprogramming. Similar results were achieved with the Src kinase inhibitor dasatinib, which reversibly suppresses CAR signaling. The degree of functional reinvigoration was proportional to the duration of rest and was associated with expression of transcription factors TCF1 and LEF1. This work demonstrates that transient cessation of CAR-T cell signaling can enhance anti-tumor potency by preventing or reversing exhaustion and challenges the paradigm that exhaustion is an epigenetically fixed state.

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“…158,159 This raises the possibility that Nr4a family members collectively may play additional undiscovered roles in B cell tolerance. Indeed, recent work shows that the Nr4a family plays a role in down-modulating T cell responses to chronic antigen stimulation by engaging the exhaustion program in CD8 T cells and the "anergy program" in CD4 T cells that receive signal one without co-stimulation.…”

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

“…Indeed, recent work shows that the Nr4a family plays a role in down-modulating T cell responses to chronic antigen stimulation by engaging the exhaustion program in CD8 T cells and the "anergy program" in CD4 T cells that receive signal one without co-stimulation. 158,159 This raises the possibility that Nr4a family members collectively may play additional undiscovered roles in B cell tolerance. To unmask redundancy among this three-member family, conditional elimination of multiple family members will be necessary.…”

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

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Efficient mechanisms of central tolerance, including receptor editing and deletion, prevent highly self-reactive B cell receptors (BCRs) from populating the periphery.Despite this, modest self-reactivity persists in (and may even be actively selected into) the mature B cell repertoire. In this review, we discuss new insights into mechanisms of peripheral B cell tolerance that restrain mature B cells from mounting inappropriate responses to endogenous antigens, and place recent work into historical context. In particular, we discuss new findings that have arisen from application of a novel in vivo reporter of BCR signaling, Nur77-eGFP, expression of which scales with the degree of self-reactivity in both monoclonal and polyclonal B cell repertoires. We discuss new and historical evidence that self-reactivity is not just tolerated, but actively selected into the peripheral repertoire. We review recent progress in understanding how dual expression of the IgM and IgD BCR isotypes on mature naive follicular B cells tunes responsiveness to endogenous antigen recognition, and discuss how this may be integrated with other features of clonal anergy. Finally, we discuss how expression of Nur77 itself couples chronic antigen stimulation with B cell tolerance. K E Y W O R D Sanergy, B cell, IgD, IgM, Nur77/Nr4a1, tolerance Previous work from our laboratory exploiting an in vivo reporter of antigen recognition, Nur77-eGFP BAC Tg, addresses this important point ( Figure 1A). 15 GFP expression in this reporter line is under the control of the regulatory region of Nr4a1/ Nur77. Nr4a1-3 encode a small family of orphan nuclear hormone receptors which were originally cloned as signal-dependent primary response genes (also known as immediate-early genes), and are highly upregulated by a range of mitogens, including antigen receptor stimulation. [16][17][18] Consequently, antigen stimulation rapidly triggers reporter expression in B and T cells in vitro ( Figure 1B), and GFP is also induced by infection or immunization in antigen-specific lymphocytes in

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NR4A transcription factors limit CAR T cell function in solid tumours

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Cited by 617 publications

References 46 publications

Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis

Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

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