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关键词： Glucocorticoids   T cells   Immunosuppression   IL-2 signaling   TCR signaling   Jak/STAT pathway   Erk1/2 activation   I kappa B activation  

摘要： BackgroundGlucocorticoids (GCs) are highly effective anti-inflammatory drugs that suppress T-cell activation, cytokine production, and T-cell proliferation. Nevertheless, at which molecular level and how fast GCs exert their immunosuppressive effect in T cells still remains elusive, as inconsistent genomic and non-genomic mechanisms of action have been proposed. One model postulates that GCs quickly inhibit proximal T-cell receptor (TCR) signaling via a non-genomic mechanism, whereas others have shown a strong inhibition of interleukin-2 (IL-2) transcription at later stages of T-cell activation. Due to their therapeutic significance, we have decided to shed light onto this issue and investigated how fast and at which level GCs inhibit T-cell activation by analyzing TCR and IL-2 *** utilized primary human T cells isolated from healthy donors, which were stimulated with immobilized CD3/CD28 antibodies. These cells were treated with three different GCs, diflorasone, dexamethasone, and *** of signaling kinetics revealed that GCs did not affect early TCR signaling as suggested by the normal phosphorylation levels of lymphocyte-specific protein tyrosine kinase (Lck), zeta-chain-associated protein kinase 70 (Zap70), linker for activation of T cells (LAT), and unchanged Ca2+ influx. Conversely, we found that GCs strongly and rapidly suppressed the activation of the Janus kinase (Jak)/ signal transducer and activator of transcription (STAT) pathway within 4-6 h upon CD3/CD28 stimulation in primary human T cells. This observation was in line with a strong inhibition of cytokine production and with the impaired upregulation of the IL-2 receptor (IL-2R) upon GC treatment, thus resulting in the abrogation of T-cell *** study, by showing that GCs rapidly suppress the IL-2/IL-2R expression and signaling without significantly affecting proximal TCR signaling, has highlighted a clear mechanism of action of GCs that co

关键词： Th1/Th2   细胞因子   宫颈癌   预测价值   Th1/Th2   Cytokines   Cervical Cancer   Predictive Value  

摘要： 目的：探讨术前Th1/Th2细胞因子与宫颈癌预后的预测价值。方法：回顾性收集2015年1月至2019年10月临沂市肿瘤医院收入手术治疗的FIGO2009 IB1~IIA2期宫颈癌患者265例临床病理资料。收集术前Th1/Th2细胞因子[γ干扰素(IFN-γ)、白介素-4 (IL-4)]。根据纳入患者随访期间生存、死亡情况，将患者分为生存组(223例)、死亡组(42例)。建立受试者工作特征(ROC)曲线得到上述指标最佳cut-off值，并分为高、低水平组。比较两组间临床病理资料。采用Kaplan-Meier法进行生存分析，采用COX回归分析可能影响患者术后5年生存的因素。结果：在入组的265例宫颈癌患者中，死亡患者共42例，死亡率为15.85%。ROC曲线分析显示，IL-4、IFN-γ的最佳cut-off值分别为3.04、3.83。COX回归分析显示，IL-4、IFN-γ的水平状态与生存率显著相关(P < 0.05)。结论：对于宫颈癌患者而言，Th1/Th2细胞因子水平有一定的生存率预测价值。

摘要： Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1, 2-3. However, the molecular mechanisms that regulate CAR-NK cell activity remain unclear. Here we identify the transcription factor cyclic AMP response element modulator (CREM) as a crucial regulator of NK cell function. Transcriptomic analysis revealed a significant induction of CREM in CAR-NK cells during the peak of effector function after adoptive transfer in a tumour mouse model, and this peak coincided with signatures of both activation and dysfunction. We demonstrate that both CAR activation and interleukin-15 signalling rapidly induce CREM upregulation in NK cells. Functionally, CREM deletion enhances CAR-NK cell effector function both in vitro and in vivo and increases resistance to tumour-induced immunosuppression after rechallenge. Mechanistically, we establish that induction of CREM is mediated by the PKA-CREB signalling pathway, which can be activated by immunoreceptor tyrosine-based activation motif signalling downstream of CAR activation or by interleukin-15. Finally, our findings reveal that CREM exerts its regulatory functions through epigenetic reprogramming of CAR-NK cells. Our results provide support for CREM as a therapeutic target to enhance the antitumour efficacy of CAR-NK cells.

关键词： Huangqi fuling decoction   Gastric cancer   Invasion   Apoptosis   Network pharmacology  

摘要： Gastric cancer (GC) is a prevalent digestive tract malignancy, and Huangqi Fuling decoction (HF) has shown potential in enhancing immune function and exhibiting anti-GC activity. However, its mechanisms remain unclear. This study utilized network pharmacology, molecular docking, and in vitro experiments to preliminarily explore the mechanisms by which HF inhibits gastric cancer invasion and metastasis while promoting apoptosis. Public databases identified differentially expressed genes (DEGs), HF targets, and GC-related genes. GO and KEGG analyses revealed signaling pathways. Clinical relevance, immune infiltration, immunotherapy, and molecular docking of hub genes were analyzed. Eight hub genes-PTGS2, MMP9, SELE, CCL2, VCAM1, ICAM1, CXCL2, and CXCL10-associated with the TNF signaling pathway were identified. HF inhibits the invasion and metastasis of GC cells by down-regulating MMP9 and PTGS2 expression, while inducing apoptosis by suppressing BCL-2 expression and promoting BAX expression. Additionally, HF can arrest the cell cycle, blocking AGS cells in the S phase and HGC-27 cells in the G0/G1 phase. This study confirms that HF promotes apoptosis and inhibits metastasis and invasion in GC cells, primarily by modulating the TNF signaling pathway. Additionally, the anti-tumor effects of HF on GC may involve immune regulatory mechanisms, but the mechanism require further experimental verification.

摘要： Interferon-gamma (IFN-gamma) plays complex and, sometimes, contradictory roles in cancer, which can affect patient responses to treatments such as immunotherapies. We recently demonstrated that IFN-gamma production by chimeric antigen receptor (CAR) T cells is not required for efficacy in hematologic tumor models, whereas IFN-gamma receptor (IFN-gamma R) signaling in solid tumor cells facilitates CAR T cell adhesion and antigen-specific cytotoxicity. Here, we show that IFN-gamma induces apoptosis of CAR T cells bearing a CD28 intracellular signaling domain, which can be reduced through targeting of IFN-gamma or IFN-gamma R. In hematologic malignancies, knockout of IFN-gamma R (IFN-gamma RKO) in CAR T cells increased their persistence without compromising efficacy. In xenograft and syngeneic solid tumor models, IFN-gamma R knockout CAR T cells displayed more potent tumor control, prolonged survival, and improved T cell memory that conferred protection from tumor rechallenge. RNA sequencing of tumor-infiltrating IFN-gamma RKO CAR T cells derived from tumor-bearing mice revealed increased cell death in tumor cells. Collectively, these data show that inhibition of IFN-gamma signaling can increase the expansion and antitumor activity of CD28-based CAR T cells in liquid and solid tumors.

关键词： hepatitis B virus   hepatocellular carcinoma   HLA-DR+ tumor cells   immunosuppressive   tumor microenvironment  

摘要： Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with hepatitis B virus (HBV) as a major driver. Despite the pivotal role of viral infections in shaping the tumor microenvironment (TME), the mechanistic differences among HBV-, hepatitis C virus (HCV)-, and non-B non-C (NBNC)-associated HCC remain poorly understood. By integrating the largest publicly available single-cell RNA sequencing (scRNA-seq) dataset of HCC (160 samples from 124 patients) with multi-scale protein-level validation using multiplex immunofluorescence and tissue microarrays (198 HCC specimens), HLA-DR+ tumor cells are identified as a distinctive feature of HBV+HCC. These tumor cells uniquely express MHC class II molecules, typically restricted to antigen-presenting cells, and correlate with immune checkpoint activation and PD-L1 expression, potentially contributing to an immunosuppressive microenvironment specific to HBV+HCC. Trajectory analysis revealed distinct CD8(+) T-cell differentiation pathways in HBV+HCC, characterized by enhanced exhaustion and stem-like phenotypes. HLA-DR+ tumor cells are associated with increased recruitment of CD8(+) T cells and correlated with T-cell exhaustion, potentially contributing to a suppressive TME. Clinically, high proportions of HLA-DR+ tumor cells are linked to poor survival outcomes, especially when accompanied by elevated PD-L1 expression, suggesting that HLA-DR+ tumor cells may serve as a potential predictive biomarker for immunotherapy efficacy in HCC. Collectively, the findings highlight HLA-DR+ tumor cells as a distinctive feature of HBV-associated HCC (HBV+HCC), providing novel insights into possible immunosuppressive mechanisms and therapeutic targets for immunotherapy in this disease context.

关键词： Aβ   amyloid β peptide   Aβ   40   amyloid β peptide 40   Aβ   42   amyloid β peptide 42   ABC   ammonium bicarbonate   AD   Alzheimer’s disease   ADAM10   a disintegrin and metalloproteinase 10   ADAM17   a disintegrin and metalloproteinase 17   AGC   automatic gain control   APLP1   amyloid β precursor like protein 1   APP   amyloid-β precursor protein   ATV   antibody transport vehicle   BACE1   β-site APP cleaving enzyme 1   BACE2   β-site APP cleaving enzyme 2   BSG   basigin   CACHD1   VWFA and cache domain-containing protein 1   CHL1   neural cell adhesion molecule L1-like protein   CNTN2   contactin-2   CSF   cerebrospinal fluid   DDA   data-dependent acquisition   DIA   data-independent acquisition   DTT   dithiothreitol   FDR   false discovery rate   IAA   iodoacetamide   IL6ST   interleukin-6 receptor subunit β   ITGA4   integrin α-4   L1CAM   neural cell adhesion molecule L1   LC-MS/MS   liquid chromatography-coupled tandem mass spectrometry   LFQ   label-free quantification   LRRN1   leucine-rich repeat neuronal protein 1   NHP   non-human primate   PASEF   parallel accumulation-serial fragmentation   QARIP   quantitative analysis of regulated intramembrane proteolysis   RSV   respiratory syncytial virus   sAPPα   soluble APPα   sAPPβ   soluble APPβ   SEZ6   seizure protein 6 homolog   SEZ6L   seizure 6-like protein   SP3   single-pot, solid-phase-enhanced sample preparation   sVCAM-1   soluble VCAM-1   TfR   transferrin receptor   TMEM27   transmembrane protein 27   TNF   tumor necrosis factor   VCAM1   vascular cell adhesion protein 1 (gene name)   VCAM-1   vascular cell adhesion protein 1 (protein name)   VEGFR3   vascular endothelial growth factor receptor 3   VLA-4   very late antigen-4  

摘要： The β-secretase β-site APP cleaving enzyme 1 (BACE1) is a major drug target for Alzheimer's disease (AD). Clinically tested BACE1 inhibitors induced unexpected cognitive side effects that may stem from their cross-inhibition of the homologous protease BACE2. Yet, little is known about BACE2 functions and substrates in vivo and no biomarker is available allowing to monitor the extent of BACE2 inhibition in vivo, in particular in cerebrospinal fluid (CSF). To identify a potential CSF biomarker for monitoring BACE2 activity, we analyzed the CSF proteome changes of non-human primates after treatment with a BACE1-selective inhibitor (a brain-targeted monoclonal antibody) in comparison to verubecestat, a clinically tested small molecule drug inhibiting both BACE1 and BACE2. Acute treatment with either the antibody or verubecestat similarly reduced CSF abundance of the cleavage products of several known BACE1 substrates, including SEZ6, gp130 and CACHD1, demonstrating similar target engagement in vivo. One CSF protein, vascular cell adhesion protein 1 (VCAM-1), was only reduced upon inhibition with verubecestat, but not upon BACE1-selective inhibition with the antibody. We conclude that VCAM-1 is a promising biomarker candidate for monitoring BACE2 inhibition in CSF, which is instrumental for the development of BACE1-selective inhibitors for the prevention of AD.