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

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^hi population. This reduction had little effect on CAR T cell proliferation but strongly augmented CAR T cell cytokine production and cytotoxicit

SUBMITTER: Hu W 

PROVIDER: S-EPMC11028344 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature