Single-cell and spatial analysis reveals macrophage-T cell crosstalk in non-small cell lung cancer immunosuppression

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Background: The tumor microenvironment (TME) is instrumental in facilitating immune evasion and promoting tumor progression in non-small cell lung cancer (NSCLC). However, the spatial heterogeneity and molecular interactions between immune and non-immune cells are not yet fully understood. This research amalgamated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic data to examine the cellular composition, ligand-receptor (LR) interactions, and immunosuppressive mechanisms of NSCLC. Methods: ScRNA-seq was performed on NSCLC tumors and paired adjacent normal tissues to analyze immune and stromal cell heterogeneity. Spatial transcriptomics was applied to consecutive tissue sections to map the distribution of major cell types and their interactions. Cell clustering, a differential gene expression analysis, and LR interaction modeling were used to identify key immune regulatory pathways. In vitro co-culture experiments were performed for functional validation. Results: A total of 28,496 high-quality single cells were analyzed, and significant differences in immune cell composition between the tumor and normal tissues were found. The NSCLC tumors exhibited a notable increase in tumor-associated macrophages (TAMs) and fibroblasts, as well as a decrease in the presence of cytotoxic T cells and natural killer (NK) cells. Notably, spatial transcriptomics revealed that the TAMs were predominantly localized in the tumor cores, where they interacted with T cells via immunosuppressive LR pairs. The SPP1-CD44 and NECTIN2-TIGIT axes were identified as major immunosuppressive pathways, with the SPP1 secreted by the TAMs contributing to immune evasion. Additionally, the HLA-E-CD8B interactions were significantly upregulated, suggesting a potential mechanism of antigen presentation modulation. The functional validation showed that SPP1 overexpression (OE) enhanced PDCD1 and CD160 expression, further confirming its role in shaping the immunosuppressive microenvironment. Conclusions: This study established a high-resolution immune atlas of NSCLC, identifying novel macrophage-T cell interactions that drive immune suppression. Our findings suggest that targeting the SPP1-CD44, NECTIN2-TIGIT, and HLA-E-CD8B pathways may improve immune responses in NSCLC. These findings provide novel therapeutic targets and highlight the potential for combination immunotherapies to overcome macrophage-mediated immune evasion.

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