Inosine induces stemness features in CAR-T cells and enhances potency

Klysz, Dorota D.; Fowler, Carley; Malipatlolla, Meena; Stuani, Lucille; Freitas, Katherine A.; Chen, Yiyun; Meier, Stefanie L.; Dániel, Bence; Sándor, Katalin; Xu, Peng; Huang, Jing; Labanieh, Louai; Keerthi, Vimal; Leruste, Amaury; Bashti, Malek; Mata-Alcazar, Janette; Gkitsas, Nikolaos; Guerrero, Justin A.; Fisher, Chris; Patel, Sunny; Asano, Kyle; Patel, Shabnum; Davis, Kara L.; Satpathy, Ansuman T.; Feldman, Steven A.; Sotillo, Elena; Mackall, Crystal L.

doi:10.1016/j.ccell.2024.01.002

articleCancer CellJan 25, 2024HYBRID OA

Inosine induces stemness features in CAR-T cells and enhances potency

DDDorota D. Klysz CFCarley Fowler MMMeena Malipatlolla LSLucille Stuani KAKatherine A. Freitas

Stanford University · Gladstone Institutes · +2 more institutions

PubMed

Indexed incrossrefpubmed

Abstract

CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO…

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135

total citations

FWCI: 34.37
Percentile: 100%
References: 76

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Authors

27

Topics & keywords

Topics

Keywords

Glutaminolysis
Cell biology
Autophagy
Reprogramming
Potency
Tumor microenvironment
Inosine
Cancer research

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