‘Nur'turing tumor T cell tolerance and exhaustion: novel function for Nuclear Receptor Nur77 in immunity

Abstract

The nuclear receptor Nur77 is expressed in a multitude of tissues, regulating cell differentiation and homeostasis. Dysregulation of Nur77 signaling is associated with cancer, cardiovascular disease, and disorders of the CNS. The role of Nur77 in T cells has been studied for almost 30 years now. There is a clear appreciation that Nur77 is crucial for apoptosis of self‐reactive T cells. However, the regulation and function of Nur77 in mature T cells remains largely unclear. In an exciting development, Nur77 has been recently demonstrated to impinge on cancer immunotherapy involving chimeric antigen receptor (CAR) T cells and tumor infiltrating lymphocytes (TILs). These studies indicated that Nur77 deficiency reduced T cell tolerance and exhaustion, thus raising the effectiveness of immune therapy in mice. Based on these novel insights, it may be proposed that regulation of Nur77 activity holds promise for innovative drug development in the field of cellular immunotherapy in cancer. In this review, we therefore summarize the role of Nur77 in T cell selection and maturation; and further develop the idea of targeting its activity in these cells as a potential strategy to augment current cancer immunotherapy treatments.

Kidins220 promotes thymic iNKT cell development by reducing TCR signals, but enhances TCR signals in splenic iNKT cells

“…Indeed, Ras, being part of the Erk pathway, is involved in iNKT development, since expression of a dominant negative Ras led to reduced iNKT cell numbers (Hu et al, 2011). The function of Kidins220 to couple the TCR to calcium influx is in line with the fact that Nur77 transcription relies not only on TCR-mediated signals, but that calcium signaling was the most important player (Liu, 2009;Youn Hong-Duk, Chatila Talal A., 2000;Lith et al, 2020). Kidins220's putative binding to a negative regulator of TCR signaling in developing iNKT cells remains speculative.…”

NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance*

“…43 This provocative expression pattern along with evidence from transcriptional and epigenetic profiling of exhausted T cells formed the rationale to investigate the role of the NR4A family in peripheral T cell tolerance. 2,18 Anjana Rao and colleagues reported that the NR4A family is upregulated by NFAT and collectively contribute to CD8 T cell exhaustion in the context of solid tumor responses, forming a positive feedback loop with TOX TFs to do so. 2,103 They show that TKO CAR T cells efficiently clear solid tumors by evading exhaustion, and that these TKO cells exhibit an altered epigenetic landscape in which bZIP (AP-1) and NF-kB sites are enriched in regions of accessible chromatin.…”

“…Moreover, Nr4a2 and Nr4a3 expression in T cells are exclusively NFAT dependent 43 . This provocative expression pattern along with evidence from transcriptional and epigenetic profiling of exhausted T cells formed the rationale to investigate the role of the NR4A family in peripheral T cell tolerance 2,18 . Anjana Rao and colleagues reported that the NR4A family is upregulated by NFAT and collectively contribute to CD8 T cell exhaustion in the context of solid tumor responses, forming a positive feedback loop with TOX TFs to do so 2,103 .…”

NR4A1-3 nuclear receptor activity and immune cell dysregulation in rheumatic diseases

“…Consistent with findings that NR4A2 is expressed by macrophage cells in RA ST and in several models of murine autoimmune joint disease, treatment of monocyte and macrophage cells with diverse mediators including lipopolysaccharide (LPS), cytokines, growth factors or oxidized lipids triggers the transcriptional induction of all three NR4A (38, 54). It is recognized that NR4A1-3 stimulus-and cell context-dependent activities, controlling pathological processes (through genomic and non-genomic actions), are influenced by their relative expression levels, subcellular localization, interactions with co-factor proteins and changes in cellular metabolism (39,63,77).…”