Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy

  • Immunity. 2022 Nov 8;55(11):2059-2073.e8. doi: 10.1016/j.immuni.2022.09.014.
Dominic Denk  1 ,  Valentina Petrocelli  2 ,  Claire Conche  2 ,  Moritz Drachsler  3 ,  Paul K Ziegler  4 ,  Angela Braun  5 ,  Alena Kress  2 ,  Adele M Nicolas  6 ,  Kathleen Mohs  2 ,  Christoph Becker  7 ,  Markus F Neurath  7 ,  Henner F Farin  8 ,  Christian J Buchholz  5 ,  Pénélope A Andreux  9 ,  Chris Rinsch  9 ,  Florian R Greten  10
Affiliations
  • 1. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany; Department of Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt/Main, Germany.
  • 2. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany.
  • 3. Department of Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt/Main, Germany.
  • 4. Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt/Main, Germany.
  • 5. Molecular Biotechnology and Gene Therapy, Paul-Ehrlich Institut, Langen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 6. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt/Main, Germany.
  • 7. Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany.
  • 8. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt/Main, Germany.
  • 9. Amazentis SA, EPFL Innovation Park, Lausanne, Switzerland.
  • 10. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt/Main, Germany. Electronic address: [email protected].
PMID: 36351375 DOI: 10.1016/j.immuni.2022.09.014
Abstract

T memory stem cells (TSCM) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. TSCM cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8+ T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced TSCM formation depended on Pink1-mediated Mitophagy triggering cytosolic release of the mitochondrial Phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking Mitophagy to TSCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy.

Keywords
T(SCM); anti-tumor immunity; mitophagy.
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