dc.contributor.author | Otano, I | en_US |
dc.contributor.author | Escors, D | en_US |
dc.contributor.author | Schurich, A | en_US |
dc.contributor.author | Singh, H | en_US |
dc.contributor.author | Robertson, F | en_US |
dc.contributor.author | Davidson, BR | en_US |
dc.contributor.author | Fusai, G | en_US |
dc.contributor.author | Vargas, FA | en_US |
dc.contributor.author | Tan, ZMD | en_US |
dc.contributor.author | Aw, JYJ | en_US |
dc.contributor.author | Hansi, N | en_US |
dc.contributor.author | Kennedy, PTF | en_US |
dc.contributor.author | Xue, S-A | en_US |
dc.contributor.author | Stauss, HJ | en_US |
dc.contributor.author | Bertoletti, A | en_US |
dc.contributor.author | Pavesi, A | en_US |
dc.contributor.author | Maini, MK | en_US |
dc.date.accessioned | 2019-02-22T17:49:58Z | |
dc.date.available | 2018-08-10 | en_US |
dc.date.issued | 2018-11-07 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/55510 | |
dc.description.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. | en_US |
dc.format.extent | 2553 - 2566 | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Mol Ther | en_US |
dc.rights | This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). | |
dc.subject | 3D models | en_US |
dc.subject | HBV | en_US |
dc.subject | HCC | en_US |
dc.subject | PD-1 | en_US |
dc.subject | TCR-redirected T cells | en_US |
dc.subject | anti-tumor immunity | en_US |
dc.subject | cell therapy | en_US |
dc.subject | checkpoints | en_US |
dc.subject | genetic modification | en_US |
dc.subject | immunotherapy | en_US |
dc.subject | shRNA knockdown | en_US |
dc.title | Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver. | en_US |
dc.type | Article | |
dc.rights.holder | (c) 2018 The Authors. | |
dc.identifier.doi | 10.1016/j.ymthe.2018.08.013 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/30217730 | en_US |
pubs.issue | 11 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 26 | en_US |
dcterms.dateAccepted | 2018-08-10 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |