(1) Background: Single-cell RNA sequencing (scRNA-seq) data are useful for decoding cell-cell communication. CellCall is a tool that is used to infer inter- and intracellular communication pathways by integrating paired ligand-receptor (L-R) and transcription factor (TF) activities from steady-state data and thus cannot directly handle two-condition comparisons. For tumor and healthy status, it can only individually analyze cells from tumor or healthy tissue and examine L-R pairs only identified in either tumor or healthy controls, but not both together. Furthermore, CellCall is highly affected by gene expression specificity in tissues. (2) Methods: CellCallEXT is an extension of CellCall that deconvolutes intercellular communication and related internal regulatory signals based on scRNA-seq. Information on Reactome was retrieved and integrated with prior knowledge of L-R-TF signaling and gene regulation datasets of CellCall. (3) Results: CellCallEXT was successfully applied to examine tumors and immune cell microenvironments and to identify the altered L-R pairs and downstream gene regulatory networks among immune cells. Application of CellCallEXT to scRNA-seq data from patients with deficiency of adenosine deaminase 2 demonstrated its ability to impute dysfunctional intercellular communication and related transcriptional factor activities. (4) Conclusions: CellCallEXT provides a practical tool to examine intercellular communication in disease based on scRNA-seq data.
Keywords: cell–cell interaction; ligand–receptor–transcription factor axis; single-cell RNA-seq.