biostudies-literatureUnknown10(1)Sachdeva MEndowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRα gene (TRAC_CAR), and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRAC_CAR T cell cytotoxicity and extends survivalNature communications5100https://www.ebi.ac.uk/biostudies/studies/S-EPMC6853973biostudies-literatureRepurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality.PMC6853973Poirot LJuillerat AJahangiri BGautron ASSachdeva MDepil SWilliams ATemburni SDuchateau PBusser BWMarechal AValton JfalseRepurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality.Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRα gene (TRAC_CAR), and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRAC_CAR T cell cytotoxicity and extends survival2019-01-01T00:00:00Z2019 Nov2025-05-29T20:18:02.403Z2025-05-29T20:18:02.403ZS-EPMC68539733172313210.1038/s41467-019-13088-3