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

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Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver
Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver
Journal Title:
Molecular Therapy
Publication Date:
01 November 2018
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.
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Funding Info:
This work was funded by a Wellcome Senior Investigator Award ( 101849/Z/13/Z ) and Medical Research Council UK grant ( G0801213 ) to M.K.M. I.O. was funded by an EASL post-doctoral fellowship, D.E. is funded by a Miguel Servet Fellowship ( CP12/03114 , Insituto de Salud Carlos III , Spain), H.S. is funded by an LRF Programme grant, and A.P. is funded by a National Research Foundation (NRF) grant ( NRF-CRP17-2017-06 ).
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