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http://purl.uniprot.org/citations/32111241http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/32111241http://www.w3.org/2000/01/rdf-schema#comment"

Background

T cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T cell exhaustion could serve as potential targets for delaying the process and improving ICI efficacy.

Methods

We analyzed the single-cell transcriptome data derived from human melanoma and non-small cell lung cancer (NSCLC) samples and classified the tumor-infiltrating (TI) CD8+ T cell population based on PDCD1 (PD-1) levels, i.e., PDCD1-high and PDCD1-low cells. Additionally, we identified differentially expressed genes as candidate factors regulating intra-tumoral T cell exhaustion. The co-expression of candidate genes with immune checkpoint (IC) molecules in the TI CD8+ T cells was confirmed by single-cell trajectory and flow cytometry analyses. The loss-of-function effect of the candidate regulator was examined by a cell-based knockdown assay. The clinical effect of the candidate regulator was evaluated based on the overall survival and anti-PD-1 responses.

Results

We retrieved many known factors for regulating T cell exhaustion among the differentially expressed genes between PDCD1-high and PDCD1-low subsets of the TI CD8+ T cells in human melanoma and NSCLC. TOX was the only transcription factor (TF) predicted in both tumor types. TOX levels tend to increase as CD8+ T cells become more exhausted. Flow cytometry analysis revealed a correlation between TOX expression and severity of intra-tumoral T cell exhaustion. TOX knockdown in the human TI CD8+ T cells resulted in downregulation of PD-1, TIM-3, TIGIT, and CTLA-4, which suggests that TOX promotes intra-tumoral T cell exhaustion by upregulating IC proteins in cancer. Finally, the TOX level in the TI T cells was found to be highly predictive of overall survival and anti-PD-1 efficacy in melanoma and NSCLC.

Conclusions

We predicted the regulatory factors involved in T cell exhaustion using single-cell transcriptome profiles of human TI lymphocytes. TOX promoted intra-tumoral CD8+ T cell exhaustion via upregulation of IC molecules. This suggested that TOX inhibition can potentially impede T cell exhaustion and improve ICI efficacy. Additionally, TOX expression in the TI T cells can be used for patient stratification during anti-tumor treatments, including anti-PD-1 immunotherapy."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.org/dc/terms/identifier"doi:10.1186/s13073-020-00722-9"xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Kim K."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Kim D.H."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Park S.Y."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Park S."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Kim H.R."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Lee I."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Kim G."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Park S.M."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Ha S.J."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Park Y.M."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Cho J.W."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/author"Koh Y.W."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/date"2020"xsd:gYear
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/name"Genome Med"xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/pages"22"xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/title"Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer."xsd:string
http://purl.uniprot.org/citations/32111241http://purl.uniprot.org/core/volume"12"xsd:string
http://purl.uniprot.org/citations/32111241http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/32111241
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