Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that ...epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal-epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.
Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis ...factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.
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•TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation•Activation of NF-κB by TNF-α induces CSN5 expression leading to PD-L1 stabilization•CSN5 enzyme activity controls T cell suppression via PD-L1 deubiquitination•Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy
Lim et al. show that inflammation increases PD-L1 expression in tumors through TNF-α-mediated activation of NF-κB, leading to transactivation of CSN5. CSN5 reduces PD-L1 ubiquitination and stabilizes it. Inhibition of CSN5 cooperates with anti-CTLA4 to enhance anti-tumor T cell function and reduce tumor growth.
Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like ...breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2
in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2
in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.
Lockdown is an effective nonpharmaceutical intervention to reduce coronavirus disease 2019 (COVID-19) transmission, but it restricts daily activity. We aimed to investigate the impact of lockdown on ...pediatric body weight and body mass index (BMI).
The systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. Four online databases (EMBASE, Medline, the Cochrane Library and CINAHL) were searched.
The pooled results showed that lockdown was associated with significant body weight gain (MD 2.67, 95% CI 2.12-3.23;
< 0.00001). The BMI of children with comorbidities or obesity did not change significantly. The BMI of general population was significantly higher during lockdown than before the pandemic (MD 0.94, 95% CI 0.32-1.56;
= 0.003). However, heterogeneity was high (I
= 84%). Among changes in weight classification, increases in the rates of obesity (OR 1.23, 95% CI 1.10-1.37;
= 0.0002) and overweight (OR 1.17, 95% CI 1.06-1.29;
= 0.001) were reported.
Our meta-analysis showed significant increases in body weight and BMI during lockdown among school-age children and adolescents. The prevalence of obesity and overweight also increased. The COVID-19 pandemic worsened the burden of childhood obesity.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that can affect nearly every organ system in the body. Besides genetic and environmental factors, unbalanced ...pro‐inflammatory and anti‐inflammatory cytokines contribute to immune dysregulation, trigger an inflammatory response, and induce tissue and organ damage. Inflammatory responses in SLE can be promoted and/or maintained by the availability of cytokines that are overproduced systemically and/or in local tissues. Several key cytokines have been considered potential targets for the reduction of chronic inflammation in SLE. Recent studies indicated that dysregulated production of several cytokines, including those of the IL‐1 family and IL‐10 family, orchestrate immune activation and self‐tolerance, play critical roles in the pathogenesis of SLE. Among IL‐1 family cytokines, IL‐1, IL‐18, IL‐33, IL‐36, IL‐37, and IL‐38 had been the most thoroughly investigated in SLE. Additionally, IL‐10 family cytokines, IL‐10, IL‐20, IL‐22, IL‐26, IL‐28, and IL‐29 are dysregulated in SLE. Therefore, a better understanding of the initiation and progression of SLE may provide suitable novel targets for therapeutic intervention. In this review, we discuss the involvement of inflammation in the pathogenesis of SLE, with a focus on IL‐1 family and IL‐10 family cytokines, and highlight pathophysiological approaches and therapeutic potential for treating SLE.
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), ...was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone.
Abstract
The predictive value of the pretreatment prognostic nutritional index (PNI) for head and neck cancer (HNC) remains controversial. We conducted a meta-analysis to assess the predictive value ...of PNI in HNC patients. A systematic search through internet databases including PubMed, Embase, and Cochrane Library for qualified studies estimating the association of PNI with HNC patient survival was performed. Overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) data were collected and evaluated. A random-effects model was used to calculate the pooled hazard ratios (pHRs) and corresponding 95% confidence intervals (CIs). A total of 7815 HNC patients from 14 eligible studies were involved. Pooled analysis showed that low pretreatment PNI was correlated with poor OS (pHR: 1.93, 95% CI 1.62–2.30,
p
< 0.001), PFS (pHR: 1.51, 95% CI 1.19–1.92,
p
= 0.008), DSS (pHR: 1.98, 95% CI 1.12–3.50,
p
< 0.001), DFS (pHR: 2.20, 95% CI 1.66–2.91,
p
< 0.001) and DMFS (pHR: 2.04, 95% CI 1.74–2.38,
p
< 0.001). Furthermore, low pretreatment PNI was correlated with poor OS despite variations in the cancer site, sample size, PNI cut-off value, analysis method (multivariate analysis or univariate analysis) and treatment modality in subgroup analysis. Elevated pretreatment PNI is correlated with a superior prognosis in HNC patients and could be used as
a biomarker in clinical practice for prognosis prediction and treatment stratification.
Epithelial-mesenchymal transition (EMT) is a pivotal mechanism for cancer dissemination. However, EMT-regulated individual cancer cell invasion is difficult to detect in clinical samples. Emerging ...evidence implies that EMT is correlated to collective cell migration and invasion with unknown mechanisms. We show that the EMT transcription factor Snail elicits collective migration in squamous cell carcinoma by inducing the expression of a tight junctional protein, claudin-11. Mechanistically, tyrosine-phosphorylated claudin-11 activates Src, which suppresses RhoA activity at intercellular junctions through p190RhoGAP, maintaining stable cell-cell contacts. In head and neck cancer patients, the Snail-claudin-11 axis prompts the formation of circulating tumour cell clusters, which correlate with tumour progression. Overexpression of snail correlates with increased claudin-11, and both are associated with a worse outcome. This finding extends the current understanding of EMT-mediated cellular migration via a non-individual type of movement to prompt cancer progression.
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