Research Scholar City of Hope National Medical Center Duarte, California, United States
Introduction/Rationale: Innate lymphoid cells (ILCs) represent a highly diverse family of lymphocytes that play pivotal roles in tissue homeostasis, inflammation, and cancer immunity. Despite growing evidence of their plasticity and functional heterogeneity, a comprehensive understanding of human ILC diversity across pathological contexts remains limited.
Methods: We performed large-scale single-cell RNA sequencing (scRNA-seq) analysis of 3,322 human samples spanning 60 physiological and pathological conditions.
Results: By integrating and harmonizing ILC transcriptomes across tissues and diseases, we systematically characterized the cellular states, transcriptional regulators, and disease-specific adaptations of ILC subsets. Our atlas reveals both conserved and disease-specific transcriptional programs of ILCs. Pathological conditions induce profound compositional and phenotypic shifts in ILC subsets. Comparative analyses between TCF7⁺ ILC1 and ZNF683⁺ NK-derived IFNG⁺ ILC1 populations highlight distinct transcription factor dependencies and microenvironmental stimuli shaping their effector programs. Notably, GZMB⁺ ILC2 cells, enriched in multiple cancer types, were associated with improved patient prognosis, suggesting a potential cytotoxic role. In contrast, NR4A1⁺ ILC3 cells within NCR⁻ ILC3 clusters were preferentially enriched in tumors and inflammatory diseases, correlating with poor prognosis and resistance to immunotherapy.
Conclusion: This comprehensive single-cell atlas delineates the dynamic landscape of human ILCs across diseases.
