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. 2022 Nov 8;55(11):2059-2073.e8.
doi: 10.1016/j.immuni.2022.09.014. Epub 2022 Oct 19.

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

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
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Free article

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

Dominic Denk et al. Immunity. .
Free article

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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Conflict of interest statement

Declaration of interests The authors have filed patents regarding the use of Urolithin in tumor therapy and CAR T cell generation. M.D. is an employee of AstraZeneca, UK. C.R. is CEO and a board member of Amazentis SA; P.A.A. is an employee of Vandria SA. F.R.G. has received consulting fees from Amazentis.

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