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

Research output: Contribution to journalArticle

Itziar Otano, David Escors, Anna Schurich, Harsimran Singh, Francis Robertson, Brian R Davidson, Giuseppe Fusai, Frederick A Vargas, Zhi M D Tan, Jia Y J Aw, Navjyot Hansi, Patrick T F Kennedy, Shao-An Xue, Hans J Stauss, Antonio Bertoletti, Andrea Pavesi, Mala K Maini

Original languageEnglish
Pages (from-to)2553-2566
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Volume26
Issue number11
Early online date16 Aug 2018
DOIs
Publication statusPublished - 7 Nov 2018

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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.

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