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

Denk D, Petrocelli V, Conche C, Drachsler M, Ziegler PK, Braun A, Kress A, Nicolas AM, Mohs K, Becker C, Neurath M, Farin HF, Buchholz CJ, Andreux PA, Rinsch C, Greten FR (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Immunity Elsevier

Book Volume: 55

Pages Range: 2059-2073.e8

Journal Issue: 11

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.

Authors with CRIS profile

Christoph Becker Professur für Molekulare Gastroenterologie Markus Neurath Lehrstuhl für Innere Medizin I

Involved external institutions

Georg-Speyer-Haus DE Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) DE Germany (DE) Paul Ehrlich Institute / Paul-Ehrlich-Institut – Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel (PEI) DE Germany (DE) École Polytechnique Fédérale de Lausanne (EPFL) CH Switzerland (CH)

How to cite

APA:

Denk, D., Petrocelli, V., Conche, C., Drachsler, M., Ziegler, P.K., Braun, A.,... Greten, F.R. (2022). Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy. Immunity, 55(11), 2059-2073.e8. https://doi.org/10.1016/j.immuni.2022.09.014

MLA:

Denk, Dominic, et al. "Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy." Immunity 55.11 (2022): 2059-2073.e8.

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