Single-Cell Analysis Reveals Spatial Heterogeneity of Immune Cells in Lung Adenocarcinoma

The impacts of the tumor microenvironment (TME) on tumor evolvability remain unclear. A challenge for nearly all cancer types is spatial heterogeneity, providing substrates for the emergence and evolvability of drug resistance and leading to unfavorable prognosis. Understanding TME heterogeneity among different tumor sites would provide deeper insights into personalized therapy. We found 9,992 cell profiles of the TME in human lung adenocarcinoma (LUAD) samples at a single-cell resolution. By comparing different tumor sites, we discovered high TME heterogeneity. Single-sample gene set enrichment analysis (ssGSEA) was utilized to explore functional differences between cell subpopulations and between the core, middle and edge of tumors. We identified 8 main cell types and 27 cell subtypes of T cells, B cells, fibroblasts and myeloid cells. We revealed CD4⁺ naive T cells in the tumor core that express high levels of immune checkpoint molecules and have a higher activity of immune-exhaustion signaling. CD8⁺ T cell subpopulations in the tumor core correlate with the upregulated activity of transforming growth factor-β (TGF-β) and fibroblast growth factor receptor (FGFR) signaling and downregulated T cell activity. B cell subtypes in the tumor core downregulate cytokine production. In this study, we revealed that there was immunological heterogeneity in the TME of patients with LUAD that have different ratios of immune cells and stromal cells, different functions, and various degrees of activation of immune-related pathways in different tumor parts. Therefore, clarifying the spatial heterogeneity of the tumor in the immune microenvironment can help clinicians design personalized treatments.