Identification of cytokine-induced cell communications by pan-cancer meta-analysis

Cancer immune responses are complex cellular processes in which cytokine-receptor interactions play central roles in cancer development and response to therapy; dysregulated cytokine-receptor communication may lead to pathological processes, including cancer, autoimmune diseases, and cytokine storm; however, our knowledge regarding cytokine-mediated cell-cell communication (CCI) in different cancers remains limited. The present study presents a single-cell and pan-cancer-level transcriptomics integration of 41,900 cells across 25 cancer types. We developed a single-cell method to actively express 62 cytokine-receptor pairs to reveal stable cytokine-mediated cell communications involving 84 cytokines and receptors. The correlation between the sample-based CCI profile and the interactome analysis indicates multiple cytokine-receptor modules including TGFB1, IL16ST, IL15, and the PDGF family. Some isolated cytokine interactions, such as FN1-IL17RC, displayed diverse functions within over ten single-cell transcriptomics datasets. Further functional enrichment analysis revealed that the constructed cytokine-receptor interaction map is associated with the positive regulation of multiple immune response pathways. Using public TCGA pan-cancer mutational data, co-mutational analysis of the cytokines and receptors provided significant co-occurrence features, implying the existence of cooperative mechanisms. Analysis of 10,967 samples from 32 TCGA cancer types revealed that the 84 cytokine and receptor genes are significantly associated with clinical survival time. Interestingly, the tumor samples with mutations in any of the 84 cytokines and receptors have a substantially higher mutational burden, offering insights into antitumor immune regulation and response. Clinical cancer stage information revealed that tumor samples with mutations in any of the 84 cytokines and receptors stratify into earlier tumor stages, with unique cellular compositions and clinical outcomes. This study provides a comprehensive cytokine-receptor atlas of the cellular architecture in multiple cancers at the single-cell level.