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1147-C Urolithin-A promotes CD8+ T cell-mediated cancer immunosurveillance via FOXO1 activation
  1. Pierpaolo Ginefra1,
  2. Helen Carrasco Hope2,
  3. Yi-Hsuan Chiang3,
  4. Sophie Nutten4,
  5. Stephanie Blum Sperisen4,
  6. George Coukos3 and
  7. Nicola Vannini3
  1. 1UNIL, Epalinges, Switzerland
  2. 2University of Lausanne, Epalinges, Switzerland
  3. 3University of Lausanne, Ludwig Institute for Cancer Research, Epalinges, Vaud, Switzerland
  4. 4Nestle Health Science, Lausanne, Switzerland
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background CD8+ T cells are vital for their protective roles against pathogens and cancer. Aging and cancer are known to promote defecst in the quality and quantity of functional naïve T cells thus lowering immune surveillance. Interventions aimed to improve and to sustain the quality of naïve T cells are needed for cancer immunoprevention. We recently showed that the mitochondrial modulator mitophagy inducer Urolithin-A (UroA) improves immune system function by ameliorating the mitochondrial pool in Hematopoietic Stem Cells (HSCs).1 However, the direct contribution of UroA on the homeostasis and functionality of CD8+ T cells has not been investigated.

Methods We adopted in vitro assays and in vivo tumor models to investigate the contribution of UroA in improving CD8+T quality and functionality.

Results Our current study demonstrates that orally supplemented UroA reduces tumor progression in mice in a CD8+ T-cell dependent manner. We show that preexposure to UroA enriched diet is sufficient to induce a robust antitumor response identifying UroA as an immunosurveillance agent. Notably, UroA supplementation promotes expansion of naïve CD8+ T cells in vivo. Furthermore, UroA improves cytokine production, mitochondrial activity in CD8+ T cells and promotes memory differentiation in vitro. Interestingly, we reveal the transcription factor FOXO1 as a non-mitochondrial target of UroA in CD8+ T indicating a novel mitophagy-independent UroA mode of action. Furthermore, we have optimized dosage and timing of UroA supplementation in vitro for long expansion of CD8+T cells with a superior anti-tumor in the context of adoptive T cell therapy (ACT).

Conclusions Overall, our finding provide preclinical evidence supporting the therapeutic function of UroA as novel immunomodulator to improve immunosurveillance.


  1. Mukul Girotra, Yi-Hsuan Chiang, Melanie Charmoy, Pierpaolo Ginefra, Helen Carrasco Hope, Charles Bataclan, Yi-Ru Yu, Frederica Schyrr, Fabien Franco, Hartmut Geiger, Stephane Cherix, Ping-Chih Ho, Olaia Naveiras, Johan Auwerx, Werner Held, Nicola Vannini. Nature Aging.

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