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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.
Genome Medicine ( IF 12.3 ) Pub Date : 2020-02-28 , DOI: 10.1186/s13073-020-00722-9
Kyungsoo Kim 1 , Seyeon Park 2 , Seong Yong Park 3 , Gamin Kim 4 , Su Myeong Park 4 , Jae-Won Cho 1 , Da Hee Kim 5 , Young Min Park 5 , Yoon Woo Koh 5 , Hye Ryun Kim 4 , Sang-Jun Ha 2 , Insuk Lee 1, 6
Affiliation  

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.

中文翻译:

单细胞转录组分析显示,TOX是人类癌症中T细胞衰竭的促进因子和抗PD-1反应的预测因子。

背景技术T细胞在肿瘤微环境中表现出异质的功能状态。免疫检查点抑制剂(ICIs)只能使干细胞样祖细胞耗尽的T细胞恢复活力,这表明抑制衰竭的进展将提高免疫疗法的功效。因此,促进T细胞衰竭的调节因子可以作为延迟该过程和提高ICI疗效的潜在靶标。方法我们分析了来自人黑素瘤和非小细胞肺癌(NSCLC)样本的单细胞转录组数据,并根据PDCD1(PD-1)的水平,即PDCD1对肿瘤浸润(TI)CD8 + T细胞群体进行了分类。 -高和PDCD1-低单元格。此外,我们确定差异表达的基因作为调节肿瘤内T细胞衰竭的候选因子。通过单细胞轨迹和流式细胞仪分析证实了TI CD8 + T细胞中候选基因与免疫检查点(IC)分子的共表达。候选调节剂的功能丧失作用通过基于细胞的敲低试验进行了检查。根据总生存期和抗PD-1反应评估候选调节剂的临床效果。结果我们在人黑素瘤和NSCLC的TI CD8 + T细胞的PDCD1高和PDCD1低亚群之间的差异表达基因之间检索到许多调节T细胞衰竭的已知因素。TOX是两种肿瘤类型中唯一预测的转录因子(TF)。随着CD8 + T细胞的衰竭,TOX水平会增加。流式细胞仪分析揭示了TOX表达与肿瘤内T细胞衰竭的严重程度之间的相关性。人TI CD8 + T细胞中的TOX抑制导致PD-1,TIM-3,TIGIT和CTLA-4的下调,这表明TOX通过上调癌症中的IC蛋白来促进肿瘤内T细胞的衰竭。最后,发现TI T细胞中的TOX水平可高度预测黑色素瘤和NSCLC的总体存活率和抗PD-1疗效。结论我们使用人TI淋巴细胞的单细胞转录组谱预测了涉及T细胞衰竭的调节因子。TOX通过上调IC分子促进肿瘤内CD8 + T细胞的衰竭。这表明,TOX抑制可能会阻止T细胞衰竭并改善ICI疗效。此外,TI T细胞中的TOX表达可用于包括抗PD-1免疫疗法在内的抗肿瘤治疗期间的患者分层。
更新日期:2020-04-22
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