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FIGURE 1 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 supplementation slows tumor progression in immunocompetent mice. A, Analysis of tumor growth rate of B16 tumors cells injected in immunocompetent C57/Bl6 mice fed for 4 weeks with UroA-enriched food before tumor cells injection. B, Analysis of tumor growth rate of B16 tumors cells injected in immunodeficient NSG mice fed with control or UroA-enriched diet for 4 weeks before tumor cells injection. C, Analysis of tumor growth rate of B16 tumors implanted in mice as in A and treated with or without anti-CD8 antibody. D, Schematic representation of in vivo feeding experiment followed by withdrawal condition. Mice were fed for 4 weeks with UroA-enriched or control food. Half of the mice were kept under the initial feeding condition, the other half received conventional food. One week after, B16 cells were subcutaneously injected. E, Analysis of tumor growth rate in H. F, Tumor growth rate of B16 tumors in mice as in A and treated with anti PD-1 therapy. Data are mean ± SEM. Each dot represents a biological replicate. In A, control = 6 mice, UroA = 7 mice. In B, control = 5 mice, UroA = 5 mice. In C, control = 6 mice, UroA = 7mice, control+CD8 = 6 mice, UroA+CD8 = 6 mice. In E, control and UroA = 7 mice, on/off condition = 5 mice. In F, each group has 6 mice. Data were analyzed by two-sided Student t test or by ANOVA test followed by multiple comparison test (**, P < 0.01). Representative results of two independent 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.