The Second Generation of CAR-iMACs with Enhanced Polarization, CAR-mediated Efferocytosis and Superior Potency against Solid Tumors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA884115 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21702101_1.fastq.gz | Fastqsanger.gz | |||
| SRR21702101_2.fastq.gz | Fastqsanger.gz | |||
| SRR21702102_1.fastq.gz | Fastqsanger.gz | |||
| SRR21702102_2.fastq.gz | Fastqsanger.gz | |||
| SRR21702103_1.fastq.gz | Fastqsanger.gz |
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Project description:Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ HA-CAR-T cells commonly express CD39 and CD73, which mediate proximal steps in Ado generation. Here we sought to enhance HA-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 features and potently enhanced HA-CAR-T functionality. Similarly, and to a greater extent, exposure of HA-CAR-T cells to INO augmented HA-CAR-T cell function and induced hallmark features of T cell stemness. INO induced profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency HA-CAR-T cell products meeting criteria for clinical dosing. These results 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.
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