Cancer cell · 2024
Inosine induces stemness features in CAR-T cells and enhances potency.
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Klysz Dorota D, Fowler Carley, Malipatlolla Meena, Stuani Lucille, Freitas Katherine A, Chen Yiyun, Meier Stefanie, Daniel Bence, Sandor 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
Аннотация
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ 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 generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.