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Nat Commun DOI:10.1038/s41467-022-29205-8

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

Publication TypeJournal Article
Year of Publication2022
AuthorsJoung, J, Kirchgatterer, PC, Singh, A, Cho, JH, Nety, SP, Larson, RC, Macrae, RK, Deasy, R, Tseng, Y-Y, Maus, MV, Zhang, F
JournalNat Commun
Volume13
Issue1
Pages1606
Date Published2022 Mar 25
ISSN2041-1723
Abstract

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.

DOI10.1038/s41467-022-29205-8
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35338135?dopt=Abstract

Alternate JournalNat Commun
PubMed ID35338135
Grant List1DP1-HL141201 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /