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FIGURE 3 from Urolithin-A Promotes CD8+ T Cell–mediated Cancer Immunosurveillance via FOXO1 Activation

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posted on 2024-05-03, 14:20 authored by Pierpaolo Ginefra, Helen Carrasco Hope, Yi-Hsuan Chiang, Sophie Nutten, Stephanie Blum, George Coukos, Nicola Vannini

UroA induces FOXO1 transcriptional activity in CD8+ T cell. A, Quantification of FOXO1 target genes in CD8+ T cells culture with 5 µmol/L UroA in IL15/7 condition in vitro. Values are expressed as fold change compare with control condition. B, Analysis of FOXO1 target genes expression levels in CD8+ T cells isolated from mice fed with control or UroA-enriched food for 4 weeks. Values are expressed as fold change compare with control condition. C, FOXO1 phosphorylation in CD8+ T cells treated for 24 hours with 5 µmol/L UroA in vitro. D, FOXO1 phosphorylation in CD8+ T isolated from mice fed with control or UroA diet. E, Representative confocal images of CD8+ T cells stained with FOXO1 (green) CD8 (red), and DAPI (blue) under the indicated culture condition (scale bar, 5 µm) in vitro (UroA = 5 µmol/L). The LUT images represent FOXO1 intensity staining (left). Quantification of nuclear FOXO1 in control and UroA (5 µmol/L) treated CD8+ T cells) in vitro (right). F, Akt S473 phosphorylation in CD8+ T cells treated for 24 hours with 5 µmol/L UroA in vitro and then stimulated with CD3/CD28 antibodies for 30 minutes (Act condition). Data are mean ± SEM. Each dot represents a biological replicate. In A, sample size n = 6. In B, sample size n = 5. In C, sample size n = 8. In D, sample size n = 5. In E, control = 72, UroA = 68. In F, sample size n = 4. Data were analyzed by two-sided Student t test (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001). Representative results of at least two independent experiments or two pooled experiments.

Funding

Swiss Cancer Research Foundation (Swiss Cancer Research)

Nestlé S.A. | Nestlé Health Science (Nestlé Health Science S.A.)

History

ARTICLE ABSTRACT

Naïve T cells are key players in cancer immunosurveillance, even though their function declines during tumor progression. Thus, interventions capable of sustaining the quality and function of naïve T cells are needed to improve cancer immunoprevention.In this context, we studied the capacity of Urolithin-A (UroA), a potent mitophagy inducer, to enhance T cell–mediated cancer immunosurveillance.We discovered that UroA improved the cancer immune response by activating the transcription factor FOXO1 in CD8+ T cell. Sustained FOXO1 activation promoted the expression of the adhesion molecule L-selectin (CD62L) resulting in the expansion of the naïve T cells population. We found that UroA reduces FOXO1 phosphorylation favoring its nuclear localization and transcriptional activity. Overall, our findings determine FOXO1 as a novel molecular target of UroA in CD8+ T cells and indicate UroA as promising immunomodulator to improve cancer immunosurveillance. Urolithin-A, a potent mitophagy inducer, emerges as a promising tool to enhance cancer immunosurveillance by activating the FOXO1 transcription factor in CD8+ T cells. This activation promotes the expansion of naïve T cells, offering a novel avenue for improving cancer immune response and highlighting UroA as a potential immunomodulator for bolstering our body's defenses against cancer.