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T-cell exhaustion is one of the main reasons of tumor immune escape. Using single-cell transcriptome data of CD8+ T cells in multiple cancers, we identified different cell types, in which Pre_exhaust and exhausted T cells participated in negative regulation of immune system process. By analyzing the coexpression network patterns and differentially expressed genes of Pre_exhaust, exhausted, and effector T cells, we identified 35 genes related to T-cell exhaustion, whose high GSVA scores were associated with significantly poor prognosis in various cancers. In the differentially expressed genes,  RGS1  showed the greatest fold change in Pre_exhaust and exhausted cells of three cancers compared with effector T cells, and high expression of  RGS1  was also associated with poor prognosis in various cancers. Additionally, RGS1 protein was upregulated significantly in tumor tissues in the immunohistochemistry verification. Furthermore,  RGS1  displayed positive correlation with the 35 genes, especially highly correlated with  PDCD1 ,  CTLA4 ,  HAVCR2 , and  TNFRSF9  in CD8+ T cells and cancer tissues, indicating the important roles of  RGS1  in CD8+ T-cell exhaustion. Considering the GTP-hydrolysis activity of  RGS1  and significantly high mRNA and protein expression in cancer tissues, we speculated that  RGS1  potentially mediate the T-cell retention to lead to the persistent antigen stimulation, resulting in T-cell exhaustion. In conclusion, our findings suggest that RGS1 is a new marker and promoting factor for CD8+ T-cell exhaustion and provide theoretical basis for research and immunotherapy of exhausted cells.

Single-Cell Transcriptome Analysis Reveals RGS1 as a New Marker and Promoting Factor for T-Cell Exhaustion in Multiple Cancers