Single‐Cell RNA‐Seq of T Cells in B‐ALL Patients Reveals an Exhausted Subset with Remarkable Heterogeneity

Wang, Xiaofang; Chen, Yanjuan; Li, Zongcheng; Huang, Bingyan; Xu, Ling; Lai, Jing; Lu, Yuhong; Zha, Xianfeng; Liu, Bing; Lan, Yu; Li, Yangqiu

doi:10.1002/advs.202101447

Cited by 36 publications

(30 citation statements)

References 63 publications

(88 reference statements)

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“…These regions can be enriched from single-cell transcriptomes while maintaining cell barcodes to integrate TCR sequencing data with gene expression profiles (18)(19)(20). Recently, TCR sequencing has been applied to solid and blood cancers to tie cell phenotypes to TCR properties, which has allowed for a deeper examination of T-cell subsets via multiple modalities (20)(21)(22). These studies also investigate the phenomenon of T-cell exhaustion, which occurs when cells enter a dysfunctional state in which they lose effector functions, such as proliferation and cytotoxicity, and gain immunoregulatory functions (7,23,24).…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

et al. 2022

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The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

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Section: Introductionmentioning

confidence: 99%

Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

et al. 2022

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“…Moreover, AML patients had a trend toward increased mature NK cells (NK CD56 (dim) cells) ( Tang et al, 2020 ). We also found DC-STAMP expression had a correlation with PDCD1 , CD274 , CTLA-4 , and TIGIT which were exhaustion markers of T cells and considered a dysfunction of anti-tumor immunity ( Noviello et al, 2019 ; Wang et al, 2021 ). A recent study showed that PD1-positive/CD8-positive T cells were higher in relapsed AML patients, compared with newly diagnosed AML patients ( Williams et al, 2019 ).…”

Section: Discussionmentioning

confidence: 72%

High Expression of DC-STAMP Gene Predicts Adverse Outcomes in AML

et al. 2022

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Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy with poor prognosis. We explored the RNA sequence data and clinical information of AML patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database to search for the core molecule for prognosis. The DC-STAMP expression was significantly higher in AML patients, which was linked to old age, unfavorable cytogenetic risk, and death (all p < 0.05). Furthermore, it was revealed that high DC-STAMP expression was an independent unfavorable factor for overall survival (OS) by univariate analysis [hazard ratio (HR): 2.683; 95% confidence interval (CI): 1.723–4.178; p < 0.001] and multivariate analysis (HR: 1.733; 95% CI: 1.079–2.781; p = 0.023). The concordance index (C-index 0.734, 95% CI: 0.706–0.762), calibration curves, and decision curve analysis showed the certain predictive accuracy of a nomogram model based on multivariate analysis for OS. In addition, we found that the differentially expressed gene (DEG) enrichment pathways of high- and low-DC-STAMP expression group enrichment pathways were focused on channel activity and platelet alpha granule by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), while gene set enrichment analysis (GSEA) pathways were mainly involved in mTORC1 signaling and TNF-α signaling via the NF-kB pathway. Moreover, a protein–protein interaction (PPI) network demonstrated that DC-STAMP interacted with two hub genes (PPBP and PF4), which were highly regulated and associated with poor survival. Finally, high DC-STAMP expression showed a significantly positive correlation with four immune cell [NK CD56 (dim) cells, macrophages, cytotoxic cells, and CD8 (+) T cells] infiltration and high level of immune checkpoint genes (PDCD1, CD274, CTLA-4, and TIGIT). Therefore, our results suggest that high expression of DC-STAMP predicts adverse outcomes for AML patients.

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“…The heterogeneity of immune checkpoint protein expression is related to the effects of immunotherapy, and the heterogeneity of exhausted T cells may be a reason for the lower effects of immunotherapy with PD‐1 inhibitors (Jia et al, 2018; Wang et al, 2021; Williams et al, 2019). In this study, we characterized the profile of TOX expression and co‐expression with PD‐1, Tim‐3, and CD244 in different AML subtypes by using a heatmap to demonstrate the global distribution.…”

Section: Discussionmentioning

confidence: 99%

Increased TOX expression concurrent with PD‐1, Tim‐3, and CD244 expression in T cells from patients with acute myeloid leukemia

Huang

Liang

Zhao

et al. 2021

Cytometry Part B Clinical

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Background T cell dysregulation is a common event in leukemia. Recent findings have indicated that aberrant expression of immune checkpoint proteins may be associated with disease relapse and progression in acute myeloid leukemia (AML). TOX, a transcription factor in the HMG‐box protein superfamily, was found to be a potential target for immunotherapy not only in solid tumors but also in hematological malignancies. However, little is known about TOX expression and co‐expression with immune checkpoint proteins or the exhausted phenotype in the T cell subsets in AML. Thus, in this study, we analyzed TOX expression and co‐expression with PD‐1, Tim‐3, and CD244 in T cells. Methods TOX expression and co‐expression with PD‐1, Tim‐3, and CD244 in CD3+, CD4+, regulatory T (Treg), and CD8+ T cells were analyzed by multi‐color fluorescent flow cytometry in peripheral blood (PB) and bone marrow (BM) samples from patients with de novo AML and AML in complete remission (CR) and healthy individuals (HIs). Results A significantly increased percentage of TOX+CD3+, CD4+, and CD8+ T cells was found in PB from patients with de novo AML in comparison with HIs. Double‐positive TOX+CD244+, TOX+PD‐1+, and TOX+Tim‐3+ T cells markedly increased in the CD3+, CD4+, and CD8+ T cell populations in de novo AML patients compared with HIs, and similar trends were demonstrated for TOX+Tim‐3+CD3+/CD4+/CD8+ T cells in de novo AML compared with AML‐CR patients. In addition, the number of TOX+, TOX+PD‐1+, and TOX+Tim‐3+Treg cells significantly increased in de novo AML patients compared with HIs, and TOX+PD‐1+Treg cells were higher in de novo AML compared with AML‐CR patients. Moreover, TOX positively correlated with Tim‐3 expression in CD8+ and Treg cells, and a positive correlation between the expression of TOX+ CD4+ and CD244+CD4+ T cells was found. Furthermore, an increased percentage of TOX+Tim‐3+ T cells in BM was also found in de novo AML patients compared with HIs. Conclusions Increased TOX concurrent with PD‐1, Tim‐3, and CD244 in T cells may contribute to T cell exhaustion and impair their function in AML. Such exhausted T cells may be partially revised when AML patients achieve CR after chemotherapy. TOX may be considered a potential target for reversing T cell exhaustion and improving T cell function in AML.

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Single‐Cell RNA‐Seq of T Cells in B‐ALL Patients Reveals an Exhausted Subset with Remarkable Heterogeneity

Cited by 36 publications

References 63 publications

Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

High Expression of DC-STAMP Gene Predicts Adverse Outcomes in AML

Increased TOX expression concurrent with PD‐1, Tim‐3, and CD244 expression in T cells from patients with acute myeloid leukemia

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