|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Joung, J, Kirchgatterer, PC, Singh, A, Cho, JH, Nety, SP, Larson, RC, Macrae, RK, Deasy, R, Tseng, Y-Y, Maus, MV, Zhang, F|
|Date Published||2022 Mar 25|
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.
|Alternate Journal||Nat Commun|
|Grant List||1DP1-HL141201 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /|