Emerging roles of p53 and other tumour-suppressor genes in immune regulation

Muñoz‐Fontela, César; Mandinova, Anna; Aaronson, Stuart A.; Lee, Sam W.

doi:10.1038/nri.2016.99

Cited by 280 publications

(263 citation statements)

References 193 publications

(221 reference statements)

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“…As expected, intrathecal treatment with si-PUMA and PFT-α exerted similar effects on preventing increased p53 and caspase 3 protein expressions. Additionally, the broader role of p53 in integrating with inflammatory pathways via NF-κB transcription has been reported [11]. Consistent with our study, comparable anti-inflammatory effects were also observed in rats injected with si-PUMA and PFT-α, as similar preservations of BSCB integrity and decreased protein levels of NF-κB and cytokines IL-1β and TNF-α were observed.…”

Section: Discussionsupporting

confidence: 92%

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Chen

et al. 2018

J Neuroinflammation

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BackgroundIschaemia reperfusion (IR) induces multiple pathophysiological changes. In addition to its classical role in regulating tumourigenesis, the feedback loop formed by p53 and its driven target p53-upregulated modulator of apoptosis (PUMA) was recently demonstrated to be the common node tightly controlling various cellular responses during myocardial IR. However, the roles of the p53-PUMA feedback loop in the spinal cord remain unclear. This study aimed to elucidate the roles of p53-PUMA feedback interactions in the spinal cord after IR, specifically investigating their regulation of caspase 3-mediated apoptosis and nuclear factor (NF)-κB-mediated cytokine release.MethodsSD rats subjected to 12 min of aortic arch occlusion served as IR models. Neurological assessment as well as p53 and PUMA mRNA and protein expression analyses were performed at 12-h intervals during a 48-h reperfusion period. The cellular distributions of p53 and PUMA were determined via double immunofluorescence staining. The effects of the p53-PUMA feedback loop on modulating hind-limb function; the number of TUNEL-positive cells; and protein levels of caspase 3, NF-κB and cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α, were evaluated by intrathecal treatment with PUMA-specific or scramble siRNA and pifithrin (PFT)-α. Blood-spinal cord barrier (BSCB) breakdown was examined by Evans blue (EB) extravasation and water content analyses.ResultsIR induced significant behavioural deficits as demonstrated by deceased Tarlov scores, which displayed trends opposite those of PUMA and p53 protein and mRNA expression. Upregulated PUMA and p53 fluorescent labels were widely distributed in neurons, astrocytes and microglia. Injecting si-PUMA and PFT-α exerted significant anti-apoptosis effects as shown by the reduced number of TUNEL-positive cells, nuclear abnormalities and cleaved caspase 3 levels at 48 h post-IR. Additionally, p53 colocalized with NF-κB within the cell. Similarly, injecting si-PUMA and PFT-α exerted anti-inflammatory effects as shown by the decreased NF-κB translocation and release of IL-1β and TNF-α. Additionally, injecting si-PUMA and PFT-α preserved the BSCB integrity as determined by decreased EB extravasation and spinal water content. However, injecting si-Con did not induce any of the abovementioned effects.ConclusionsInhibition of aberrant p53-PUMA feedback loop activation by intrathecal treatment with si-PUMA and PFT-α prevented IR-induced neuroapoptosis, inflammatory responses and BSCB breakdown by inactivating caspase 3-mediated apoptosis and NF-κB-mediated cytokine release.

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Section: Discussionsupporting

confidence: 92%

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Chen

et al. 2018

J Neuroinflammation

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“…29 Nonetheless, it has become clear that p53 also participates in various aspects of immune modulation in cancer. 30 In the present study, we are reporting that introducing functional wtp53 gene via SGT-53 can induce immunogenic changes of cancer cells, effectively promote anti-tumor immunity, and reduce tumor-induced immunosuppression in the TME. By augmenting anti-PD1 immune checkpoint blockade, the SGT-53 was able to convert mouse syngeneic tumors that were relatively insensitive to anti-PD1 into tumors that were more responsive to anti-PD1 therapy.…”

Section: Discussionmentioning

confidence: 80%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

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“…5 Moreover, the use of p53 inhibitors, such as Pifithrin-β, has been approved in clinical trials to attenuate the side effects of chemotherapy. 9 Given the described adverse impact of disrupting p53 in TECs and in T cells,5 the therapeutic use of p53 inhibitors must be implemented with care to safeguard the balance between immune reconstitution and tolerance induction.…”

Section: A01/00mentioning

confidence: 99%

“…Yet recent studies have revealed alternative roles for p53 in immunoregulation and autoimmunity. 5 In relation to the thymic epithelium, the observations that the p53 homolog p63 controls the turnover of TEC progenitors 6 imply a possible functional relationship within the p53 family. The analysis of the role of p53 in TEC physiology has been precluded because of its broad expression pattern and the complex phenotype of germline p53-null mice, which ultimately develop thymic lymphomas.…”

mentioning

confidence: 99%

Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice

Rodrigues

Ribeiro

Perrod³

et al. 2017

Blood

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Key points:• TEC-intrinsic ablation of p53 predominantly affects medullary TECs, altering their RANK-driven differentiation and transcriptome.• Loss of p53 in TECs couples disrupted thymopoiesis to altered T-cell homeostasis and tolerance Thymic epithelial cells (TECs) provide crucial microenvironments for T-cell development and tolerance induction. As the regular function of the thymus declines with age, it is of fundamental and clinical relevance to decipher new determinants that control TEC homeostasis in vivo. Beyond its recognized tumor suppressive function, p53 controls several immunoregulatory pathways. To study the cell-autonomous role of p53 in thymic epithelium functioning, we developed and analyzed mice with conditional inactivation of Trp53 in TECs (p53cKO). We report that loss of p53 primarily disrupts the integrity of medullary TEC (mTEC) niche, a defect that spreads to the adult cortical TEC compartment. Mechanistically, we found that p53 controls specific and broad programs of mTEC differentiation. Apart from restraining the expression and responsiveness of the receptor activator of NF-kB (RANK), which is central for mTEC differentiation, deficiency of p53 in TECs altered multiple functional modules of the mTEC transcriptome, including tissuerestricted antigen expression. As a result, p53cKO mice presented premature defects in mTEC-dependent regulatory T-cell differentiation and thymocyte maturation, which progressed to a failure in regular and regenerative thymopoiesis and peripheral Tcell homeostasis in the adulthood. Lastly, peripheral signs of altered immunological tolerance unfold in mutant mice and in immunodeficient mice that received p53cKO-derived thymocytes. Our findings position p53 as a novel molecular determinant of thymic epithelium function throughout life.Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 IntroductionWithin the thymus, thymic epithelial cells (TECs) orchestrate the development of functionally diverse and self-tolerant T cells. 1 Importantly, impaired TEC functions arise with aging, cytoablative regimens and infection, which compromise T-cell responses to pathogens, and vaccination in the elderly, and patients undergoing bone marrow transplantation (BMT) or chemotherapy. Equally, failures in TEC-mediated tolerance induction lead to autoimmunity. 2 Hence, the identification of novel regulators of TEC homeostasis is crucial to comprehend the foundations of immunity and to intervene medically in disorders linked to a dysfunctional thymus.Cortical TECs (cTECs) and medullary TECs (mTECs) define 2 functionally distinct microenvironments, which differentiate from bipotent TEC progenitors. 1 Whereas cTECs drive T-cell lineage specification and positive selection, mTECs promote the maturation of positively selected thymocytes, regulatory T-c...

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Emerging roles of p53 and other tumour-suppressor genes in immune regulation

Cited by 280 publications

References 193 publications

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice

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