The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and ...immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1
TIM-3
T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3
cytotoxic CD8 T cells and immunosuppressive regulatory T cells (T
cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes T
cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon β and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.
Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. BAY 11–7085 (BAY), which is a well-known IκBα inhibitor, suppressed viability in cancer ...cells via induction of ferroptotic death in an NF-κB-independent manner. Reactive oxygen species scavenging, relief of lipid peroxidation, replenishment of glutathione and thiol-containing agents, as well as iron chelation, rescued BAY-induced cell death. BAY upregulated a variety of Nrf2 target genes related to redox regulation, particularly heme oxygenase-1 (HO-1). Studies with specific inhibitors and shRNA interventions suggested that the hierarchy of induction is Nrf2−SLC7A11−HO-1. SLC7A11 inhibition by erastin, sulfasalazine, or shRNA interference sensitizes BAY-induced cell death. Overexperession of SLC7A11 attenuated BAY-inhibited cell viability. The ferroptotic process induced by hHO-1 overexpression further indicated that HO-1 is a key mediator of BAY-induced ferroptosis that operates through cellular redox regulation and iron accumulation. BAY causes compartmentalization of HO-1 into the nucleus and mitochondrion, and followed mitochondrial dysfunctions, leading to lysosome targeting for mitophagy. In this study, we first discovered that BAY induced ferroptosis via Nrf2−SLC7A11−HO-1 pathway and HO-1 is a key mediator by responding to the cellular redox status.
•BAY 11–7085 induces ferroptotic cell death regardless of IκBα−NF-κB signaling.•BAY 11–7085 triggers ferroptosis through a Nrf2−SLC7A11−HO-1 signaling pathway.•HO-1 mediates redox regulation of ferroptotic death.•HO-1 causes endoplasmic reticulum stress and mitophagy.
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.
With H2O or NH3 stimuli, the blue cobalt‐based metal–organic framework (MOF) BP can reversibly transform to red RP. The removal/recovery of terephthalate ligands accompanied by the transformation ...leads to a gate effect, which allows the encapsulation and release of small solvent molecules under certain conditions. This is the first example of topology transformation from a self‐penetrating to interpenetrating net in 3D MOFs.
Lung adenocarcinoma (ADC) is the predominant histological type of lung cancer, and radiotherapy is one of the current therapeutic strategies for lung cancer treatment. Unfortunately, biological ...complexity and cancer heterogeneity contribute to radioresistance development. Karyopherin α2 (KPNA2) is a member of the importin α family that mediates the nucleocytoplasmic transport of cargo proteins. KPNA2 overexpression is observed across cancer tissues of diverse origins. However, the role of KPNA2 in lung cancer radioresistance is unclear. Herein, we demonstrated that high expression of KPNA2 is positively correlated with radioresistance and cancer stem cell (CSC) properties in lung ADC cells. Radioresistant cells exhibited nuclear accumulation of KPNA2 and its cargos (OCT4 and c‐MYC). Additionally, KPNA2 knockdown regulated CSC‐related gene expression in radioresistant cells. Next‐generation sequencing and bioinformatic analysis revealed that STAT1 activation and nuclear phospholipid scramblase 1 (PLSCR1) are involved in KPNA2‐mediated radioresistance. Endogenous PLSCR1 interacting with KPNA2 and PLSCR1 knockdown suppressed the radioresistance induced by KPNA2 expression. Both STAT1 and PLSCR1 were found to be positively correlated with dysregulated KPNA2 in radioresistant cells and ADC tissues. We further demonstrated a potential positive feedback loop between PLSCR1 and STAT1 in radioresistant cells, and this PLSCR1‐STAT1 loop modulates CSC characteristics. In addition, AKT1 knockdown attenuated the nuclear accumulation of KPNA2 in radioresistant lung cancer cells. Our results collectively support a mechanistic understanding of a novel role for KPNA2 in promoting radioresistance in lung ADC cells.
Nuclear KPNA2 promotes radioresistance and regulates cancer stem cell properties in lung adenocarcinoma cells. A loop between PLSCR1 and STAT1 is involved in KPNA2‐mediated radioresistance.
Most cases of oral squamous cell carcinoma (OSCC) develop from visible oral potentially malignant disorders (OPMDs). The latter exhibit heterogeneous subtypes with different transformation ...potentials, complicating the early detection of OSCC during routine visual oral cancer screenings. To develop clinically applicable biomarkers, we collected saliva samples from 96 healthy controls, 103 low-risk OPMDs, 130 high-risk OPMDs, and 131 OSCC subjects. These individuals were enrolled in Taiwan’s Oral Cancer Screening Program. We identified 302 protein biomarkers reported in the literature and/or through in-house studies and prioritized 49 proteins for quantification in the saliva samples using multiple reaction monitoring-MS. Twenty-eight proteins were successfully quantified with high confidence. The quantification data from non-OSCC subjects (healthy controls + low-risk OPMDs) and OSCC subjects in the training set were subjected to classification and regression tree analyses, through which we generated a four-protein panel consisting of MMP1, KNG1, ANXA2, and HSPA5. A risk-score scheme was established, and the panel showed high sensitivity (87.5%) and specificity (80.5%) in the test set to distinguish OSCC samples from non-OSCC samples. The risk score >0.4 detected 84% (42/50) of the stage I OSCCs and a significant portion (42%) of the high-risk OPMDs. Moreover, among 88 high-risk OPMD patients with available follow-up results, 18 developed OSCC within 5 y; of them, 77.8% (14/18) had risk scores >0.4. Our four-protein panel may therefore offer a clinically effective tool for detecting OSCC and monitoring high-risk OPMDs through a readily available biofluid.
Feature selection is a process aimed at filtering out unrepresentative features from a given dataset, usually allowing the later data mining and analysis steps to produce better results. However, ...different feature selection algorithms use different criteria to select representative features, making it difficult to find the best algorithm for different domain datasets. The limitations of single feature selection methods can be overcome by the application of ensemble methods, combining multiple feature selection results. In the literature, feature selection algorithms are classified as filter, wrapper, or embedded techniques. However, to the best of our knowledge, there has been no study focusing on combining these three types of techniques to produce ensemble feature selection. Therefore, the aim here is to answer the question as to which combination of different types of feature selection algorithms offers the best performance for different types of medical data including categorical, numerical, and mixed data types. The experimental results show that a combination of filter (i.e., principal component analysis) and wrapper (i.e., genetic algorithms) techniques by the union method is a better choice, providing relatively high classification accuracy and a reasonably good feature reduction rate.
Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling ...initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6-activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined with anti-T cell immunoglobulin mucin-3 (anti-Tim-3) therapy in animal models. A positive correlation between IL-6 and PD-L1 expression was also observed in hepatocellular carcinoma patient tumor tissues. These results identify a mechanism regulating PD-L1 glycosylation initiation and suggest the combination of anti-IL-6 and anti-Tim-3 as an effective marker-guided therapeutic strategy.
Based on the newly designed ligand 4′‐(3,5‐dicarboxyphenyl)‐4,2′:6′,4′′‐terpyridine (DCTP), a unique semi‐conductive 3D framework {CuΙCuΙΙ2(DCTP)2NO3⋅1.5 DMF}n (1) with a narrow band gap of 2.1 eV, ...was obtained and structurally characterized. DFT calculations with van de Waals correction employed to explore the electronic structure of 1, clearly revealed its semi‐conductive behavior. Furthermore, we found that 1 exhibits a superior band alignment with water to produce hydrogen and degrade organic pollutants. Without adding any photosensitizers, 1 displays an efficiently photocatalytic hydrogen production in water based on the photo‐generated electrons under UV/Vis light. 1 also exhibits excellent photo‐degradation of methyl blue under visible‐light owing to the strong oxidization of excited holes. It is the first example of MOFs with doubly photocatalytic activities related to photo‐generated electrons and holes, respectively.
Narrow band gap: The metal–organic framework (MOF) {CuΙCuΙΙ2(DCTP)2NO3⋅1.5 DMF}n has a narrow band gap of 2.1 eV and is a semiconductor. Theoretical and experimental investigations confirmed its performance in photocatalytic hydrogen generation and in organic‐dye degradation. It is the first report for MOFs exhibiting two different photocatalytic activities based on photo‐generated electrons and holes.
Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and ...autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.
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•AMPK activation attenuates PRC2-mediated epigenetic silencing•AMPK phosphorylates EZH2 at T311 to disrupt EZH2-SUZ12 interaction•EZH2 T311 phosphorylation inhibits PRC2 oncogenic function•EZH2 T311 phosphorylation correlates with better survival in cancer patients
The metabolic state of the cell can be connected to gene expression and modification of histones through several mechanisms. Wan et al. find that AMPK-mediated phosphorylation of EZH2 at T311 inhibits PRC2 methyltransferase activity to relieve PRC2-dependent epigenetic silencing and subsequently suppresses tumorigenesis.
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