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Microbiology and Immunology

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CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions.

TitleCRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions.
Publication TypeJournal Article
Year of Publication2019
AuthorsHu W, Zi Z, Jin Y, Li G, Shao K, Cai Q, Ma X, Wei F
JournalCancer Immunol Immunother
Volume68
Issue3
Pagination365-377
Date Published2019 Mar
ISSN1432-0851
KeywordsAnimals, Cell Line, Tumor, CRISPR-Cas Systems, Cytotoxicity, Immunologic, GPI-Linked Proteins, Humans, Immunotherapy, Adoptive, Lymphocyte Activation, Mice, Neoplasms, Experimental, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell
Abstract

The interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands on a target tumour may limit the capacity of chimeric antigen receptor (CAR) T cells to eradicate solid tumours. PD-1 blockade could potentially enhance CAR T cell function. Here, we show that mesothelin is overexpressed in human triple-negative breast cancer cells and can be targeted by CAR T cells. To overcome the suppressive effect of PD-1 on CAR T cells, we utilized CRISPR/Cas9 ribonucleoprotein-mediated editing to disrupt the programmed cell death-1 (PD-1) gene locus in human primary T cells, resulting in a significantly reduced PD-1 population. This reduction had little effect on CAR T cell proliferation but strongly augmented CAR T cell cytokine production and cytotoxicity towards PD-L1-expressing cancer cells in vitro. CAR T cells with PD-1 disruption show enhanced tumour control and relapse prevention in vivo when compared with CAR T cells with or without αPD-1 antibody blockade. Our study demonstrates a potential advantage of integrated immune checkpoint blockade with CAR T cells in controlling solid tumours and provides an alternative CAR T cell strategy for adoptive transfer therapy.

DOI10.1007/s00262-018-2281-2
Alternate JournalCancer Immunol Immunother
PubMed ID30523370
Grant List81402542 / / National Natural Science Foundation of China /
14PJ1405600 / / Scholarship of Pujiang Talents in Shanghai /

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