Long-term persistence and functionality of adoptively transferred antigen-specific T cells with genetically ablated PD-1 expression

Significance Adoptive transfer of antigen-specific T cells has shown impressive clinical success in cancer and infectious diseases. However, due to constant stimulation, the transferred cells can switch into dysfunctional states marked by the expression of programmed cell death protein 1 (PD-1). Recent breakthroughs in cell engineering enabled the precise genetic ablation of this inhibitory receptor via CRISPR/Cas9 technology. First studies have shown benefits of PD-1 knockout for T cell functionality in short-term experiments but potential loss of fitness at later stages. Here, we could show that PD-1 ablation is not necessarily detrimental for long-term functionality and persistence of engineered T cells. These findings are of particular importance since the first PD-1 KO T cell products have recently entered into the clinics.