Decipher: A computational pipeline to extract context-specific mechanistic insights from single-cell profiles

The advent of single-cell profiling technologies has revolutionized our understanding of the cellular and molecular states that underpin disease states and response to therapies. However, current computational tools cannot recover both known and novel mechanistic insights at distinct layers of biological regulation in an unbiased manner. Here, we present Decipher , a novel computational pipeline that builds integrated cell signalling networks from single-cell profiles in a context-specific, data-driven manner and identifies the key cellular and molecular events that drive disease. We benchmarked Decipher against existing tools and found it could recover known, experimentally determined cytokine signalling pathways with high accuracy, whilst maintaining the flexibility to detect novel pathways and context-specific effects. Notably, Decipher reports a manageable set of interactions that can be aggregated into global cell-to-cell signalling maps that are interpretable. In addition, we utilised Decipher to unveil the cellular and molecular mechanisms driving a novel population of inflammatory monocytes enriched with interferon stimulated genes that is markedly increased in frequency following secondary immunization with the Pfizer-BioNTech COVID-19 mRNA vaccine. Taken together, our findings demonstrate that Decipher can decode signalling pathways and report on ligand-receptor mediated transcription factor – target gene networks that underlie processes in homeostasis and disease, as well as cellular responses to therapies. We present Decipher as an invaluable new tool for the discovery of novel therapeutic targets and the development of new medicines. ### Competing Interest Statement AB is the founder of the start-up company INSiGENe Pty Ltd that funded this work. AB is a co-founder, equity holder, and director of the startup company Respiradigm Pty Ltd that is unrelated to this work. EB received a scholarship from INSiGENe Pty Ltd to conduct this work. * BCG : Bacillus Calmette-Guérin (vaccine) CBMC : Cord Blood Mononuclear Cells CCC : Cell-Cell Communication CT : Cell Type D LR : Decipher Score for Ligand-Receptor Interaction ERP : Estrogen Receptor Positive GRN : Gene Regulatory Network ICB : Immune Checkpoint Blockade ICU : Intensive Care Unit IFNG : Interferon Gamma iSN : Integrated Signalling Network LR : Ligand-Receptor ML : Machine Learning PBMC : Peripheral Blood Mononuclear Cells pDCs : plasmacytoid dendritic cells RCT : Receiver Cell Type SCT : Sender Cell Type scRNA-seq : Single-cell RNA sequencing TF : Transcription Factor TG : Target Gene TNBC : Triple-Negative Breast Cancer Δ TF : Change in Transcription Factor activity