Systematic identification of gene combinations to target in innate immune cells to enhance T cell activation

Lei Xia, Anastasia Komissarova, Arielle Jacover, Yehuda Shovman (), Sebastian Arcila-Barrera, Sharona Tornovsky-Babeay, Milsee Mol Jaya Prakashan, Abdelmajeed Nasereddin, Inbar Plaschkes, Yuval Nevo, Idit Shiff, Oshri Yosefov-Levi, Tamara Izhiman, Eleonora Medvedev, Elad Eilon, Asaf Wilensky, Simon Yona and Oren Parnas ()
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Lei Xia: The Hebrew University of Jerusalem
Anastasia Komissarova: The Hebrew University of Jerusalem
Arielle Jacover: The Hebrew University of Jerusalem
Yehuda Shovman: The Hebrew University of Jerusalem
Sebastian Arcila-Barrera: The Hebrew University of Jerusalem
Sharona Tornovsky-Babeay: The Hebrew University of Jerusalem
Milsee Mol Jaya Prakashan: The Hebrew University of Jerusalem
Abdelmajeed Nasereddin: The Hebrew University of Jerusalem
Inbar Plaschkes: I-CORE Bioinformatics Unit of the Hebrew University and Hadassah Medical Center
Yuval Nevo: I-CORE Bioinformatics Unit of the Hebrew University and Hadassah Medical Center
Idit Shiff: The Hebrew University of Jerusalem
Oshri Yosefov-Levi: The Hebrew University of Jerusalem
Tamara Izhiman: The Hebrew University of Jerusalem
Eleonora Medvedev: The Hebrew University of Jerusalem
Elad Eilon: The Hebrew University of Jerusalem
Asaf Wilensky: Hebrew University of Jerusalem
Simon Yona: Hebrew University
Oren Parnas: The Hebrew University of Jerusalem

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Genetic engineering of immune cells has opened new avenues for improving their functionality but it remains a challenge to pinpoint which genes or combination of genes are the most beneficial to target. Here, we conduct High Multiplicity of Perturbations and Cellular Indexing of Transcriptomes and Epitopes (HMPCITE-seq) to find combinations of genes whose joint targeting improves antigen-presenting cell activity and enhances their ability to activate T cells. Specifically, we perform two genome-wide CRISPR screens in bone marrow dendritic cells and identify negative regulators of CD86, that participate in the co-stimulation programs, including Chd4, Stat5b, Egr2, Med12, and positive regulators of PD-L1, that participate in the co-inhibitory programs, including Sptlc2, Nckap1l, and Pi4kb. To identify the genetic interactions between top-ranked genes and find superior combinations to target, we perform high-order Perturb-Seq experiments and we show that targeting both Cebpb and Med12 results in a better phenotype compared to the single perturbations or other combinations of perturbations.

Date: 2023
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DOI: 10.1038/s41467-023-41792-8

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