Comprehensive analysis of single-cell RNA-seq and bulk RNA-seq revealed the heterogeneity and convergence of the immune microenvironment in renal cell carcinoma.

Substantial progress has been made in cancer biology and treatment in recent years, but the clinical outcome of patients with renal cell carcinoma (RCC) remains unsatisfactory. The tumor microenvironment (TME) is a potential target. By analyzing single-cell RNA sequencing (sc-RNAseq) data from six RCC tumor samples, this study identified 11 different cell types in the RCC cellular microenvironment, indicating a high degree of intratumoral heterogeneity. Through re-dimensionality reduction clustering of epithelial cells, neutrophils, macrophages, and T cells, we deeply reveal differences in the RCC tumor microenvironment. By analyzing differentially expressed genes in normal epithelial cells and malignant epithelial cells, we identify RNASET2 and GATM as potential prognostic biomarkers in RCC. In addition, by transcriptional factor analysis, we found significant differences in the expression of GZMK-CD8 T cell and B cell transcription factors between cancer tissues and normal tissues. By cell correlation analysis, we found significant correlations between neutrophils and macrophages and between IL7R-CD4 T cells and T regulatory (Treg) cells in RCC, which may be involved in the formation of immune TMEs. By cell developmental trajectory analysis, we showed that macrophages may be derived from neutrophils, whereas Treg cells may be derived from IL7R-CD4 T cells. By cell communication analysis, we found a clear interaction between macrophages and endothelial cells, neutrophils, and GZMK-CD8 T cells. In addition, we found that ADGRE5 signaling was mainly derived from mast cells and GZMK-CD8 T cells, and had a significant communication effect with neutrophils. The COLLAGEN signaling pathway is mainly derived from fibroblasts and has a significant communication effect with mast cells. Finally, we verified that RNASET2, which is highly expressed in epithelial cells, promotes proliferation and migration of RCC in vitro. RNASET2 is likely to be a potential target for renal cell carcinoma therapy. The results based on sc-RNAseq data analysis help to further elucidate the cellular microenvironment of RCC and provide help for cancer heterogeneity studies. This will help to provide more accurate personalized treatment for patients in clinical diagnosis.