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CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity
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CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity
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Journal Article
CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity
2022
Overview
The cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, here we perform a genome-scale CRISPR activation screen for genes that enable human melanoma cells to evade cytotoxic T cell killing. Overexpression of four top candidate genes (
CD274
(PD-L1),
MCL1
,
JUNB
, and
B3GNT2
) conferred resistance in diverse cancer cell types and mouse xenografts. By investigating the resistance mechanisms, we find that MCL1 and JUNB modulate the mitochondrial apoptosis pathway.
JUNB
encodes a transcription factor that downregulates FasL and TRAIL receptors, upregulates the MCL1 relative BCL2A1, and activates the NF-κB pathway.
B3GNT2
encodes a poly-N-acetyllactosamine synthase that targets >10 ligands and receptors to disrupt interactions between tumor and T cells and reduce T cell activation. Inhibition of candidate genes sensitized tumor models to T cell cytotoxicity. Our results demonstrate that systematic gain-of-function screening can elucidate resistance pathways and identify potential targets for cancer immunotherapy.
Loss-of-function CRISPR-based screens have identified several genes associated with cancer resistance to T cell-induced cytotoxicity. Here the authors perform a genome-scale, gain-of-function CRISPR screen and identify candidate genes, including the poly-N-acetyllactosamine synthase B3GNT2, whose overexpression confers tumor cell resistance to T cell cytotoxicity
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/2
/ 13/31
/ 38/1
/ 38/15
/ 49
/ 49/23
/ 631/250
/ 631/67
/ 631/80
/ 82/80
/ 96
/ 96/44
/ Animals
/ Cancer
/ Clustered Regularly Interspaced Short Palindromic Repeats - genetics
/ CRISPR
/ Genes
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Melanoma
/ Mice
/ Myeloid Cell Leukemia Sequence 1 Protein - metabolism
/ N-Acetylglucosaminyltransferases - metabolism
/ N-Acetyllactosamine synthase
/ Proto-Oncogene Proteins c-bcl-2 - genetics
/ Proto-Oncogene Proteins c-bcl-2 - metabolism
/ Science
/ Toxicity
/ Tumors
