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

• DOI: 10.1016/j.immuni.2022.09.014
• Publication Date: 2022-10-19T02:56:57Z
• Authors: Dominic Denk; Valentina Petrocelli; Claire Conche; Moritz Drachsler; Paul K. Ziegler; Angela Braun; Alena Kress; Adele M. Nicolas; Kathleen Mohs; Christoph Becker; Markus F. Neurath; Henner F. Farin; Christian J. Buch...; Pénélope A. Andreux; Chris Rinsch; Florian R. Greten
• Keywords: Adoptive Cell Transfer; PINK1

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