Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 68, Issue 3, Pages 365-377Publisher
SPRINGER
DOI: 10.1007/s00262-018-2281-2
Keywords
Mesothelin; Chimeric antigen receptor; Programmed cell death protein 1; SgRNA-guided clustered regularly interspaced short palindrome repeats-associated nuclease Cas9
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Funding
- National Natural Science Foundation of China [81402542]
- Pujiang Talents in Shanghai [14PJ1405600]
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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(hi) 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 PD-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.
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