bioRxiv : the preprint server for biology · 2023
Inosine Induces Stemness Features in CAR T cells and Enhances Potency.
ПрепринтСтатьяНазвание и аннотация: Перевод в очереди
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Klysz Dorota D, Fowler Carley, Malipatlolla Meena, Stuani Lucille, Freitas Katherine A, Meier Stefanie, Daniel Bence, Sandor Katalin, Xu Peng, Huang Jing, Labanieh Louai, Leruste Amaury, Bashti Malek, Keerthi Vimal, 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
Аннотация
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.