Related Articles Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver. Mol Ther. 2018 11 07;26(11):2553-2566 Authors: Otano I, Escors D, Schurich A, Singh H, Robertson F, Davidson BR, Fusai G, Vargas FA, Tan ZMD, Aw JYJ, Hansi N, Kennedy PTF, Xue SA, Stauss HJ, Bertoletti A, Pavesi A, Maini MK Abstract Checkpoint inhibitors and adoptive cell therapy provide promising options for treating solid cancers such as HBV-related HCC, but they have limitations. We tested the potential to combine advantages of each approach, genetically reprogramming T cells specific for viral tumor antigens to overcome exhaustion by down-modulating the co-inhibitory receptor PD-1. We developed a novel lentiviral transduction protocol to achieve preferential targeting of endogenous or TCR-redirected, antigen-specific CD8 T cells for shRNA knockdown of PD-1 and tested functional consequences for antitumor immunity. Antigen-specific and intrahepatic CD8 T cells transduced with lentiviral (LV)-shPD-1 consistently had a marked reduction in PD-1 compared to those transduced with a control lentiviral vector. PD-1 knockdown of human T cells rescued antitumor effector function and promoted killing of hepatoma cells in a 3D microdevice recapitulating the pro-inflammatory PD-L1hi liver microenvironment. However, upon repetitive stimulation, PD-1 knockdown drove T cell senescence and induction of other co-inhibitory pathways. We provide the proof of principle that T cells with endogenous or genetically engineered specificity for HBV-associated HCC viral antigens can be targeted for functional genetic editing. We show that PD-1 knockdown enhances immediate tumor killing but is limited by compensatory engagement of alternative co-inhibitory and senescence program upon repetitive stimulation. PMID: 30217730 [PubMed – indexed for MEDLINE]

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Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver.