Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma

Chen, Dongping; Wang, Ning; Jiang, Ze-Zhou; Peng, Zhi-Peng; Zhu, Lingyan; Zhuang, Shi‐Mei; Kuang, Dong-Ming; Zheng, Limin; Wu, Yan

doi:10.1016/j.jhep.2019.04.007

Cited by 128 publications

(103 citation statements)

References 41 publications

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“…Proteins from cells were extracted as previously described. 76 The following antibodies were used in immunoblotting: anti-NR1H3 (Rabbit, ab176323, dilution 1:1000; Abcam), anti-TFEC (Rabbit, ab185226, dilution 1:1000; Abcam), anti-EOMES (Rabbit, 81493s, dilution 1:1000; CST), anti-RUNX3 (Rabbit, ab224641, dilution 1:1000; Abcam), anti-XBP1 (Rabbit, ab109221, dilution 1:1000; Abcam), and anti-β-actin (mouse, 3700s, dilution 1:1000; CST).…”

Section: Immunoblottingmentioning

confidence: 99%

Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma

et al. 2020

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Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A+ dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell–cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A+ DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.

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Section: Immunoblottingmentioning

confidence: 99%

Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma

et al. 2020

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“…PD-L1 expression in myeloid cells is upregulated directly by the hypoxia-inducible factor (HIF)-1α that binds to the PD-L1 promoter to induce PD-L1 transcription [ 38 ]. Furthermore, TAMs upregulate PD-L1 expression by assuming aerobic glycolysis [ 39 ] while also secreting TNFα that promotes aerobic glycolysis in cancer cells [ 40 ] and augments PD-L1 expression on myeloid cells [ 41 ]. Sustained chronic inflammation enhances PD-L1 expression on myeloid cells through the cyclooxygenase 2/prostaglandin E2 pathway [ 19 ] and interleukin (IL)-6 production [ 42 ].…”

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Shklovskaya

Rizos

2020

IJMS

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Immunotherapies blocking immune inhibitory receptors programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) on T-cells have dramatically improved patient outcomes in a range of advanced cancers. However, the lack of response, and the development of resistance remain major obstacles to long-term improvements in patient outcomes. There is significant interest in the clinical use of biomarkers to improve patient selection, and the expression of PD-1 ligand 1 (PD-L1) is often reported as a potential biomarker of response. However, accumulating evidence suggests that the predictive value of PD-L1 expression in tumor biopsies is relatively low due, in part, to its complex biology. In this review, we discuss the biological consequences of PD-L1 expression by various cell types within the tumor microenvironment, and the complex mechanisms that regulate PD-L1 expression at the genomic, transcriptomic and proteomic levels.

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“…Knockdown of MYC expression can induce PD-L1 expression both at mRNA and protein levels (Zou et al, 2018). A key glycolytic enzyme, PFKFB3, mediated the increased expression of PD-L1 via activating the nuclear factor kappa B signaling pathway in HCC (Chen et al, 2019a). Although accumulating evidences suggested the activation of EGFR contributes to PD-L1 expression in several cancers (Li et al, 2018b;Chen et al, 2019b), it is still unknown whether EGF/EGFR signal was involved in PD-L1 expression in HCC.…”

Section: Discussionmentioning

confidence: 99%

PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC

et al. 2020

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High expression of programmed death-ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) cells usually inhibits the proliferation and functions of T cells, leading to immune suppression in tumor microenvironment. However, very little has been described regarding the mechanism of PD-L1 overexpression in HCC cells. In the present study, we found epidermal growth factor (EGF) stimulation promoted the expression of PD-L1 mRNA and protein in HCC cells. Inhibition of epidermal growth factor receptor (EGFR) could reverse EGF-induced the expression of PD-L1 mRNA and protein. Subsequently, we also observed that the phosphorylation level of Pyruvate kinase isoform M2 (PKM2) at Ser37 site was also increased in response to EGF stimulation. Expression of a phosphorylation-mimic PKM2 S37D mutant stimulated PD-L1 expression as well as H3-Thr11 phosphorylation in HCC cells, while inhibition of PKM2 significantly blocked EGF-induced PD-L1 expression and H3-Thr11 phosphorylation. Furthermore, mutation of Thr11 of histone H3 into alanine abrogated EGF-induced mRNA and protein expression of PD-L1, Chromatin immunoprecipitation (ChIP) assay also suggested that EGF treatment resulted in enhanced H3-Thr11 phosphorylation at the PD-L1 promoter. In a diethylnitrosamine (DEN)-induced rat model of HCC, we found that the expression of phosphorylated EGFR, PKM2 nuclear expression, H3-Thr11 phosphorylation as well as PD-L1 mRNA and protein was higher in the livers than that in normal rat livers. Taken together, our study suggested that PKM2-dependent histone H3-Thr11 phosphorylation was crucial for EGF-induced PD-L1 expression at transcriptional level in HCC. These findings may provide an alternative target for the treatment of hepatocellular carcinoma.

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Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma

Cited by 128 publications

References 41 publications

Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma

Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC

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