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CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

ABSTRACT: CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

PROVIDER: PRJNA670003 | ENA |

REPOSITORIES: ENA

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CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

Project description:CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

| PRJNA670002 | ENA

CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

Project description: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 (sgRNA distribution)

Project description:CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity (sgRNA distribution)

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CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

Project description:The cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, 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) confer 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-B 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 sensitize 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.

2022-02-09 | PXD031532 | Pride

CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

Project description:RNA-seq data for candidate genes identified from CRISPR activation screen for tumor immune evasion

2022-02-05 | GSE159539 | GEO

CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

Project description:ChIP-seq data for candidate gene JUNB identified from CRISPR activation screen for tumor immune evasion

2022-02-05 | GSE159538 | GEO

CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-02-04 | GSE159540 | GEO

CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity (sgRNA distribution)

Project description:SgRNA library distributions of CRISPR activation screens for tumor immune evasion

2022-02-24 | GSE197309 | GEO

A genome-wide CRISPR/Cas phenotypic screen for modulators of DUX4 cytotoxicity reveals screen complications

Project description:A genome-wide CRISPR/Cas phenotypic screen for modulators of DUX4 cytotoxicity reveals screen complications

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Drivers of topoisomerase II poisoning mimic and complement cytotoxicity in AML cells

Project description:Recently approved cancer drugs remain out-of-reach to most patients due to prohibitive costs and only few produce clinically meaningful benefits. An untapped alternative is to enhance the efficacy and safety of existing cancer treatments. We hypothesized that the response to topoisomerase II poisons, the most successful group of cancer drugs, can be improved by considering treatment-associated transcript levels, taken as surrogates for protein expression. To this end, we analyzed transcriptomes from Acute Myeloid Leukemia (AML) cell lines treated with the topoisomerase II poison etoposide. Using complementary criteria of co-regulation within networks and of essentiality for cell survival, we identified and functionally confirmed 11 druggable drivers of etoposide cytotoxicity. Drivers with pre-treatment expression predicting etoposide response (e.g. PARP9) generally synergized with the drug. Drivers repressed by etoposide (e.g. PLK1) displayed standalone cytotoxicity. Drivers, whose modulation evoked etoposide-like gene expression changes (e.g. mTOR), were cytotoxic both alone and in combination with etoposide. In summary, both pre-treatment gene expression and treatment-driven changes contribute to the cell killing effect of etoposide. Inhibitors of protein products of the involved genes can be used to enhance the efficacy of etoposide. This strategy can be used to identify combination partners or even replacements for other classical anticancer drugs, especially those interfering with DNA integrity and transcription.

2019-09-18 | GSE126895 | GEO

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