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关键词： cytokine gene-modified tumor cells   interleukin-7(IL-7)   membrane-bound form   tumor cell vaccine   tumor therapy  

摘要： Various approaches employing cytokines and cytokine gene-modified tumor cells have been explored to induce antitumor responses, yet their widespread application has been limited due to efficacy concerns and adverse effects. In this study, interleukin-7 was engineered for expression both as a natural secretory form (sIL-7) and as a membrane-bound form fused with the B7.1 type I transmembrane protein (mbIL-7/B7) on CT26 colon cancer cells. Analysis of the resulting cell clones demonstrated that ectopically expressed sIL-7 and mbIL-7/B7 both retained similar capacities to induce the expansion and activation of CD8 T cells and to enhance antitumor responses in vitro. While the sIL-7 or mbIL-7/B7 clones showed similar growth in culture, the mbIL-7/B7 clone exhibited lower tumorigenicity in mice compared to the sIL-7 clone or wild-type CT26 cells. Specifically, the mbIL-7/B7 clone failed to form tumors in approximately 60% of the mice injected with it. Moreover, 80% of mice that rejected the mbIL-7/B7 clone developed long-term systemic immunity against CT26 cells. Analysis of immune cells within the tumor masses revealed significant increases in CD4 T cells, CD8 T cells, and dendritic cells in tumors formed by the mbIL-7/B7 clone compared to those formed by the sIL-7 clone. These findings suggest that the membrane-bound form of IL-7 with B7.1 is more effective than the secretory form in establishing antitumor immunity within the tumor microenvironment. Our strategy of expressing the mbIL-7/B7 chimera holds promise as a novel approach for tumor therapy, particularly in cases requiring IL-7 supplementation.

关键词： NAD+ salvage pathway   anti‐tumor necrosis factor therapy   fusobacterium nucleatum   microbiota   ulcerative colitis  

摘要： Approximately 50% of the patients with ulcerative colitis (UC) are primarily nonresponsive to anti-tumor necrosis factor (TNF) therapy or lose their responsiveness over time. The gut microbiota plays an important role in the resistance of UC to anti-TNF therapy; however, the underlying mechanism remains unknown. Here, it is found that the transplantation of gut fecal microbiota from patients with UC alters the diversity of the gut microbiota in dextran sulfate sodium-induced colitis mice and may affect the therapeutic responsiveness of mice to infliximab. Furthermore, the abundances of Romboutsia and Fusobacterium increase in the tissues of patients with UC who do not respond to anti-TNF therapy. Differentially abundant metabolites are mainly enriched in nicotinate and nicotinamide metabolism in NCM460 cells after Fusobacterium nucleatum infection. Mechanistically, F. nucleatum promotes the nicotinamide adenine dinucleotide (NAD) salvage pathway by upregulating NAMPT expression, which subsequently leads to the activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway and promotes the secretion of inflammatory factors, ultimately inhibiting the therapeutic response to anti-TNF drugs. These findings demonstrate that the gut microbiota can influence the response to anti-TNF therapy in patients with UC and highlight the therapeutic potential of targeting F. nucleatum and its associated pathways for preventing and treating drug resistance in UC.

关键词： DNA polymorphism   Nephropathy   Neuropathy   TNF-α   Type 2 diabetes  

摘要： Type 2 diabetes (T2DM) is a group of chronic and systemic metabolic diseases. Nephropathy (NP) and neuropathy (NR) are two common complications that severely affect the quality of life of patients with T2DM. In this study, our aim was to investigate the association between TNF-alpha (-308) gene polymorphism and the risk of developing NP and NR in patients with T2DM We also aimed to determine the association between TNF-alpha (-308) gene polymorphism and several demographic characteristics and biochemical parameters of patients with T2DM developed NP and/or NR. First, blood samples of patients were collected, and DNA isolation was performed. Then, real-time PCR analysis was used for genotyping the TNF-α (-308) gene utilising fluorescently labelled probes. Patients' demographical data and biochemical parameters were also obtained. Our study did not detect any significant difference in the frequency of possessing the gene polymorphism (A allele) between the groups. Additionally, no significant difference was detected when the data on various biochemical parameters were evaluated in GG, GA, and AA genotypes.

关键词： fat-associated lymphoid clusters   neutrophil extracellular traps   omentum   pre-metastatic niche  

摘要： Disseminated cancer cells in the peritoneal fluid often colonize omental fat-associated lymphoid clusters but the mechanisms are unclear. Here, we identify that innate-like B cells accumulate in the omentum of mice and women with early-stage ovarian cancer concomitantly with the extrusion of chromatin fibers by neutrophils called neutrophil extracellular traps (NETs). Studies using genetically modified NET-deficient mice, pharmacologic inhibition of NETs, and adoptive B cell transfer show that NETs induce expression of the chemoattractant CXCL13 in the pre-metastatic omentum, stimulating recruitment of peritoneal innate-like B cells that in turn promote expansion of regulatory T cells and omental metastasis through producing interleukin (IL)-10. Ex vivo studies show that NETs elicit IL-10 production in innate-like B cells by inactivating SHP-1, a phosphatase that inhibits B cell activation pathways, and by generating reactive oxygen species. These findings reveal that NETs alter immune cell dynamics in the pre-metastatic omentum, rendering this niche conducive for colonization.

关键词： Growth   HPV   IL-37   Inflammation   Oral epithelial cells  

摘要： Human papillomavirus (HPV) is the most prevalent sexually transmitted infection globally, with significant implications for various anogenital cancers, such as vulval, vaginal, anal, penile, head and neck cancers. HPV infections have been linked to the induction of inflammation. In contrast, Interleukin-37 (IL-37) is recognized as an anti-inflammatory cytokine. In this study, two distinct types of oral epithelial cells were employed to investigate the impact of HPV on inflammation. The experimental outcomes unequivocally demonstrated that human papillomavirus (HPV) elicited a pronounced and statistically significant induction of inflammatory responses within both varieties of oral epithelial cells under investigation. Interestingly, IL-37 exhibited a mitigating effect, attenuating the HPV-induced inflammation in oral epithelial cells. Further exploration into the molecular mechanisms involved revealed that knockdown (KD) of PI3K compromised the anti-inflammatory effects of IL-37 in response to HPV. Similarly, KD of AKT was found to compromise the regulatory effects of IL-37 on HPV-induced inflammation. Notably, KD of mTOR was identified as a key factor, compromising the anti-inflammatory effects of IL-37 in the context of HPV-induced inflammation. Additionally, the study uncovered that the mTOR inhibitor, rapamycin, could effectively compromise the effects of IL-37 on HPV-induced inflammation. These findings contribute valuable insights into the intricate pathogenesis of HPV-induced inflammation and may pave the way for the development of innovative treatments for this condition.

关键词： CSCs   Interleukin-10   Nasopharyngeal carcinoma   Radio resistance   STAT3  

摘要： One of the primary reasons for the failure of therapy in nasopharyngeal cancer (NPC) is radio resistance-related localized one, which may lead to tumor residuals or recurrences. Several studies have linked interleukin-10 (IL-10) to crucial functions in cancer development and response to therapy. Its function in NPC's radio resistance is, however, not well understood. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR were utilized for confirming IL-10 expression in NPC cell lines. The prognostic significance of IL-10 was also assessed via Kaplan-Meier analysis. CNE2R, a radioresistant NPC cell line, expressed IL-10 at high levels, which were also shown to be considerably elevated in individuals with radioresistant NPC, as measured by ELISA. Moreover, the levels were also linked to poor clinical outcomes and prognosis in cancer cases. We also showed some evidence of a link between hypoxia-inducible factor 1-alpha (HIF-1 A) and serum IL-10 levels in NPC. Meanwhile, we find that IL-10 is up-regulated in CSC. IL-10 enhanced the self-renewal and tumorigenesis of nasopharyngeal CSC. In terms of mechanism, IL-10 enhances nasopharyngeal CSC self-renewal and tumorigenesis by activating STAT3 pathway. In NPC, IL-10/STAT3 Axis Nasopharyngeal Carcinoma Cancer stem cell and radio resistance.

关键词： Diabetes-associated periodontitis   IL-33   Immunomodulation   Intercellular interaction   Macrophages   Periodontal ligament fibroblasts  

摘要： Tissue-resident fibroblasts with immunomodulatory properties have recently been identified as key players in inflammation. However, their roles within the periodontal niche in diabetes-associated periodontitis remain unclear. Interleukin (IL)-33, known as an "alarmin" in inflammatory responses, has recently emerged as a potential contributor to periodontitis. Herein, we show that IL-33 levels are reduced in periodontal ligament fibroblasts (PDLFs) in the in vivo models of diabetes-associated periodontitis and in vitro models of diabetic inflammation. In the in vitro co-culture model, overexpression of IL-33 in PDLFs promotes M2 macrophage polarization, while knockdown of IL-33 in PDLFs instigates M1 macrophage polarization. Notably, supplementation with IL-33 in vivosignificantly alleviates periodontal tissue destruction and enhances M2 macrophage infiltration, whereas targeting the IL-33/ST2 axis exacerbates tissue damage and promotes M1 macrophage polarization in diabetes-associated periodontitis. Additionally, theCUT&RUN assay confirms the direct regulation of IL-33 by Yes-associated protein (YAP). These findings demonstrate that IL-33 deficiency in PDLFs favors M1 macrophage polarization, thereby exacerbating the pathogenesis of diabetes-associated periodontitis. Our study underscores the essential immunomodulatory role of PDLFs in creating an inflammatory niche and unveils a novel interaction axis between PDLFs and macrophages in diabetes-associated periodontitis.

摘要： 脑胶质瘤是最常见的中枢神经系统恶性肿瘤，具有高病死率、高复发率等特征。近年来，细胞免疫治疗作为新型免疫疗法在胶质瘤中的应用前景令人瞩目。自然杀伤(NK)细胞是一类继T细胞之后具有临床应用潜能的免疫细胞，目前在抗肿瘤免疫治疗领域中引起广泛关注。嵌合抗原受体(CAR)-NK细胞治疗是一个新的癌症细胞免疫疗法，可以更加精准地杀伤癌细胞，进而起到抗肿瘤的效果。本文综述了胶质瘤基础研究中CAR-NK细胞的特色和主要治疗靶点，以及CAR-NK细胞在基础研究和临床试验中所遇到的新挑战，为基于CAR-NK细胞的胶质瘤免疫治疗提供理论依据和新的思路。

关键词： CpG methylation   Epithelial ovarian cancer   Interferon regulatory factor 1   Interleukin-6   Myeloid differentiation factor 88   Specificity protein 1  

摘要： MYD88 is an IL-6 primary response gene and, its upregulation of expression has been shown to be a poor prognostic factor in epithelial ovarian cancer (EOC). We investigated the effects of CpG methylation at the proximal promoter/5'UTR and IL-6/SP1/IRF1 signaling on upregulation of MYD88 and prognosis in EOC. We assessed CpG methylation at the proximal promoter/5'UTR of MYD88 using bisulfite sequencing/PCR in 103 EOC patients, 28 normal ovarian tissues and two EOC cell lines with differential expression of MYD88 and identified the impact of the level of CpG methylation on MYD88 upregulation by SP1/IRF1 with knockdown or blockade of IL-6. The proximal promoter/5'UTR of MYD88 was significantly hypomethylated in 75 EOC tissues compared to 28 normal ovarian tissues (P < 0.001). CpG hypomethylation was relevant to MYD88 upregulation in 75 EOC cases (R = 0.4376; P < 0.001). Of them, 38 cases with m5CpG/MYD88/IL-6 were associated with reduced progression-free/overall survival compared to 37 cases with m5CpG/MYD88/IL-6 (P < 0.01). Knockdown of IL-6 or blockade with IL-6 receptor McAb attenuated MYD88 upregulation by SP1/IRF1 signaling in EOC cells with MYD88 (P < 0.001). In conclusion, CpG hypomethylation at the proximal promoter/5'UTR contributes to MYD88 upregulation in EOC via IL-6/SP1/IRF1 pathway.