2. Academic Validation
  3. Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy

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

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.

Figures
Products