UroA promotes naïve T-cell expansion in vivo and memory formation in vitro.A, Schematic representation of in vivo feeding experiment. B, Frequency of naïve CD8+ T cells (CD62L+CD44−) isolated from the spleen of mice fed with control or UroA-enriched diet. C, Expression level of CD62 L in CD8+ T cells from B, values are normalized to the control. D, Frequency of central memory (CD62L+CD44+) in CD8+ T cells treated for 4 days with 5 µmol/L UroA in IL15/7 condition in vitro. E, Expression level of central memory marker CD62 L in C. F, Analysis of tumor growth rate of B16-Ova tumor-bearing mice adoptively transferred with no cells (saline = 13 mice), control OT-1 CD8+ T cells (control = 10 mice) and UroA-treated OT-1 CD8+ T cells (UroA = 13 mice). G, Quantification of expression level of TIM-3 and PD-1 in TILs from F measured (control = 7, UroA = 6). H, Frequency of terminally exhausted T cells (TCF1−PD1+TIM3+) from G. Data are mean ± SEM. Each dot represents a biological replicate. In B and C, control n = 10 mice, UroA = 12 mice. In D and E, sample size n = 5. Data were analyzed by two-sided Student t test (*, P < 0.05; **, P < 0.01). Representative results of 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.)
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.
