Abstract
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.
Highlights
T-cell exhaustion (Tex), a hyporesponsive state of T cells with increased inhibitory receptors, decreased effector cytokines, and impaired cytotoxicity, was originally described in CD8+ T cells during chronic lymphocytic choriomeningitis virus (LCMV) of mice [1]
Focusing on CD8+ T-cell exhaustion-associated clusters, we identified regulator of G protein signaling 1 (RGS1) as a new marker and promoting factor for T-cell exhaustion in multiple cancers with poor prognosis and showed highly positive correlation with the well-known genes associated with T-cell exhaustion
Cells in hepatocellular cancer (HCC) were identified as Tn, Teff, Pre_exhaust, Tex, MAIT, and cells in nonsmall cell lung cancer (NSCLC) that were identified as Tn, Teff, Pre_exhaust, Tex, Trm, and MAIT
Summary
T-cell exhaustion (Tex), a hyporesponsive state of T cells with increased inhibitory receptors, decreased effector cytokines, and impaired cytotoxicity, was originally described in CD8+ T cells during chronic lymphocytic choriomeningitis virus (LCMV) of mice [1]. Single-cell RNA sequencing (scRNA-seq) has clearly revealed some new mechanisms and phenomena of cancer with the advantages of high accuracy and reproducibility [8,9,10]. Using single-cell transcriptome profiling, we can identify new types of immune cells which cannot be revealed at the original tissue level and can construct a developmental trajectory for immune cells which can reveal the heterogeneity [11]. These new findings are useful to better understand the immune system and its mechanism of action on tumors. Using advantage of scRNA-seq to analyze T cells and obtain the hallmarks of exhausted T cells can bring a new therapeutic strategy on clinical cancer treatment
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