Cross-tissue single-cell landscape of neutrophil heterogeneity and immunity in health and disease 3469

Abstract Description Neutrophils, the most abundant leukocytes in human blood, play multifaceted roles in health and disease. A comprehensive landscape of neutrophil heterogeneity and immunity is not yet fully elucidated. To fully characterize neutrophils in health and disease, we collected and curated single-cell transcriptomic profiles of 1.2 million human neutrophils from 879 samples and 40 studies to generate an integrated Human Neutrophil Single-cell Atlas (HNeuSA) encompassing 7 sequencing platforms, 9 countries, over 20 tissues and over 20 diseases including viral and bacterial infection, cancer, and autoimmune diseases. We also curated over 6,000 bulk transcriptome samples from whole blood or isolated neutrophils. We identified multiple neutrophil subsets exhibiting distinct transcriptional programs spanning the spectrum of differentiation and maturation. We found significant differences in neutrophil subsets and gene expression underlying sex difference, obesity, severity of infectious diseases, and immune suppression in cancer. Importantly, we defined two neutrophil-specific gene signatures which were associated with all-cause mortality regardless of age, sex, BMI, smoking, and disease status (HR = 1.48, p = 1.6e-03). Together, HNeuSA is the largest collection of human neutrophil single-cell transcriptomics data to date, enabling in-depth investigation of neutrophil heterogeneity and immunity, and development of neutrophil-based diagnostic and prognostic tools and immunotherapy strategies. Topic Categories Computational and Systems Immunology (COMP)