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

Julia Joung (), Paul C. Kirchgatterer, Ankita Singh, Jang H. Cho, Suchita P. Nety, Rebecca C. Larson, Rhiannon K. Macrae, Rebecca Deasy, Yuen-Yi Tseng, Marcela V. Maus and Feng Zhang ()
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Julia Joung: MIT
Paul C. Kirchgatterer: MIT
Ankita Singh: MIT
Jang H. Cho: MIT
Suchita P. Nety: MIT
Rebecca C. Larson: Massachusetts General Hospital and Harvard Medical School
Rhiannon K. Macrae: MIT
Rebecca Deasy: Broad Institute of MIT and Harvard
Yuen-Yi Tseng: Broad Institute of MIT and Harvard
Marcela V. Maus: Massachusetts General Hospital and Harvard Medical School
Feng Zhang: MIT

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29205-8

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