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Mol Ther. 2018 Nov 7;26(11):2553-2566. doi: 10.1016/j.ymthe.2018.08.013. Epub 2018 Aug 16.

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

Author information

1
Division of Infection and Immunity, Institute of Immunity and Transplantation, UCL, London, UK; Division of Immunity and Immunotherapy, Centre for Applied Medical Research, Pamplona, Spain; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
2
Division of Infection and Immunity, Institute of Immunity and Transplantation, UCL, London, UK; Navarrabiomed-Biomedical Research Centre, IdiSNA, Pamplona, Spain.
3
Division of Infection and Immunity, Institute of Immunity and Transplantation, UCL, London, UK; School of Immunology and Microbial Sciences, King's College London, London, UK.
4
Division of Infection and Immunity, Institute of Immunity and Transplantation, UCL, London, UK.
5
Department of Surgery and Interventional Science, UCL, London, UK.
6
Institute of Cancer Research, UCL, London, UK.
7
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
8
Centre for Immunobiology, Blizard Institute, Bart's and the London School of Medicine and Dentistry, QMUL, London, UK.
9
Division of Infection and Immunity, Institute of Immunity and Transplantation, UCL, London, UK; Genetic Engineering Laboratory, School of Biological and Environmental Engineering, Xi'an University, Xi'an, China.
10
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore; Emerging Infectious Diseases Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
11
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore. Electronic address: andreap@imcb.a-star.edu.sg.
12
Division of Infection and Immunity, Institute of Immunity and Transplantation, UCL, London, UK. Electronic address: m.maini@ucl.ac.uk.

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.

KEYWORDS:

3D models; HBV; HCC; PD-1; TCR-redirected T cells; anti-tumor immunity; cell therapy; checkpoints; genetic modification; immunotherapy; shRNA knockdown

PMID:
30217730
PMCID:
PMC6225092
DOI:
10.1016/j.ymthe.2018.08.013
[Indexed for MEDLINE]
Free PMC Article

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