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摘要： Despite the success of immune checkpoint inhibitors in cancer, many patients do not respond or relapse following treatment. Therefore, new approaches to augment existing immunotherapies are needed. CRISPR screens have revealed the importance of TNF-α signal transduction mediators, such as TAK1, in facilitating tumor susceptibility to cytotoxic T cells. Here, we demonstrate that inhibition of TAK1 in tumor cells lowers the threshold for TNF-α-induced cytotoxicity. Upon TNF-α signaling, pharmacologic inhibition of TAK1 sensitized tumor cells to RIPK1-dependent apoptosis. However, RIPK1-independent apoptosis occurred upon genetic deletion of Tak1, suggesting a novel scaffolding function of TAK1 is required to induce RIPK1 kinase activity during cell death. Deleting Tak1 impaired in vivo tumor growth, enhanced α-PD-1 immunotherapy, and lead to durable anti-tumor memory, dependent on CD8 T cells and intact TNF-α signaling. Our results collectively demonstrate that compromising TAK1 function within tumor cells leverages the cytotoxic capacity of TNF to enhance anti-tumor immunity and generate deeper and more durable anti-tumor immune responses in preclinical models of cancer.

关键词： agonist   antibody engineering   single domain antibody   nanobody   Nb   TNF   TNFR2  

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关键词： Acute myeloid leukemia   Antithymocyte globulin   Graft-versus-host disease   Chronic graft-versus-host disease-free relapse-free survival  

摘要： Antithymocyte globulin (ATG) reduces chronic graft-versus-host disease (cGvHD), but concerns remain regarding relapse risk, particularly across cytogenetic risk groups. We retrospectively analyzed 148 acute myeloid leukemia (AML) patients in first remission who underwent matched sibling allogeneic hematopoietic stem cell transplantation (HSCT) across three centers. Patients received transplantation with or without ATG (2.5-5 mg/kg) and were stratified by cytogenetic risk (intermediate, n = 128;adverse, n = 20). Propensity score matching and inverse probability of treatment weighting were applied to adjust for baseline imbalances. After a median follow-up of 91 months, ATG use (n = 96) reduced the incidence of cGvHD (HR 0.43;95% CI 0.26-0.72;p = 0.001) and improved cGvHD-free relapse-free survival (cGRFS;HR 0.61;95% CI 0.40-0.93;p = 0.022). No significant differences were observed in overall survival, event-free survival (EFS), relapse, or non-relapse mortality. A significant interaction between ATG and cytogenetic risk (p = 0.025) indicated differential effects by risk profiles. In subgroup analyses, intermediate-risk patients derived consistent benefit, whereas adverse-risk patients (ATG n = 12;non-ATG n = 8) showed higher relapse and inferior EFS. With respect to dose, both 2.5 and 5 mg/kg reduced cGvHD relative to non-ATG;exploratory analyses suggested that 2.5 mg/kg may provide adequate prophylaxis without excess relapse, although statistical power was limited. In conclusion, ATG was associated with reduced cGvHD and improved cGRFS in HSCT for AML, with benefit mainly in intermediate-risk patients. Its use in adverse-risk AML warrants caution, as it may be associated with higher relapse.

关键词： ERAP1/ERAP2   GWAS   HLA-B*52:01   MHC-I-opathies   Takayasu arteritis   genetics  

摘要： OBJECTIVES:Takayasu arteritis is a rare vasculitis characterized by inflammation of large arteries. Given the robust genetic association with HLA-B*52:01, it was recently proposed to classify Takayasu arteritis within the spectrum of MHC-I-opathies. Although genetic associations in ERAP1 and ERAP2 have been described in several MHC-I-opathies, their role in Takayasu arteritis remains unclear. This study investigated the genetic interaction between ERAP1/ERAP2 and HLA-B*52:01 in Takayasu arteritis. METHODS:Using data from a large multi-ancestral GWAS, we examined the genetic association between ERAP1 and ERAP2 polymorphisms with Takayasu arteritis. Next, we conducted genetic interaction analyses between ERAP1/ERAP2 polymorphisms and HLA-B*52:01, followed by a meta-analysis across populations. In addition, we conducted a genetic association test for ERAP1/ERAP2 polymorphisms restricted to HLA-B*52:01-positive individuals. RESULTS:Our analyses suggested no significant genetic interactions of ERAP1 or ERAP2 with HLA-B*52:01 in Takayasu arteritis, which contrasts with the findings observed in other MHC-I-opathies. In addition, no significant associations between ERAP1/ERAP2 and Takayasu arteritis were detected, including analyses under dominant or recessive models, or after stratifying by HLA-B*52:01 status. CONCLUSION:These results suggest that the genetic profile of Takayasu arteritis differs from other MHC-I-opathies, supporting its classification as a distinct subtype within this group of immune-mediated diseases. These finding are hypothesis-generating, and validation in larger cohorts is warranted.

关键词： BDCA-2   TLR9   biomarker   immunocomplex   nucleic acids   rheumatoid arthritis   type I interferon  

摘要： OBJECTIVES:Aberrant interferon (IFN) signalling is strongly associated with rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Blood dendritic cell antigen 2 (BDCA-2) regulates IFN production in plasmacytoid dendritic cells (pDCs). While heparin inhibits IFN formation via triggering surface BDCA-2, its soluble form (solBDCA-2) antagonizes heparin and thereby drives excessive IFN formation. However, the role of solBDCA-2 in RA and SLE is unknown. This study aims to determine whether solBDCA-2 can serve as a biomarker for RA and/or SLE and provide insights into its potential role in disease mechanisms. METHODS:solBDCA-2 and IFN-α expression were analyzed by ELISA in the serum of RA (n = 14) and SLE (n = 14) patients and compared with healthy controls (n = 15). To gain mechanistic insight of solBDCA-2 in RA and SLE, we studied the interaction of solBDCA-2 with nucleic acids, its role in enhancing type I IFN production in the plasmacytoid dendritic cell line CAL-1 and in human peripheral blood mononuclear cells (hPBMCs). RESULTS:IFN-α was upregulated in patient sera of both RA and SLE. In contrast, solBDCA-2 was exclusively upregulated in the serum of RA patients, but not in patients with SLE. solBDCA-2 interacted with phosphodiester CpG-oligodeoxynucleotides (ODN) 2006, a ligand of TLR9, and poly I: C, a ligand of TLR3, to form complexes that enhance type I IFN production in CAL-1 cells and hPBMCs. CONCLUSION:These findings show that solBDCA-2 enhances type I interferon production by forming immunostimulatory complexes with DNA and RNA. Dysregulated solBDCA-2 expression might contribute to RA pathogenesis.

关键词： DEHP   小鼠   免疫毒性   过敏性鼻炎   细胞因子  

摘要： 为探讨环境污染物邻苯二甲酸二（2-乙基己基）脂（DEHP）对过敏性鼻炎（AR）的影响，37只Balb/c雄性小鼠随机分为5组，空白组、模型组和DEHP低(3 mg·kg-1)、中(30 mg·kg-1)、高(300 mg·kg-1)剂量组。实验结束时，评估各组小鼠过敏症状积分并计算脾脏指数，HE染色观察鼻黏膜组织病理学变化，并通过酶联免疫吸附试验（ELISA）检测血清中免疫球蛋白E（IgE）、特异性免疫球蛋白E（sIgE）和细胞因子的水平。结果显示，末次滴鼻激发后15 min内模型组和DEHP各剂量组小鼠打喷嚏、抓鼻子和流涕情况均增多，过敏症状累计积分均>5分，与空白组比较各组小鼠症状积分的升高均有统计学意义（P<0.05）；并且小鼠过敏症状积分随DEHP染毒剂量的增加而升高，但差异无统计学意义（P>0.05）。与空白组比较，各组血清中sIgE和IgE水平均升高（P<0.05），但除空白组外其余各组间sIgE水平的差异均无统计学意义（P>0.05），而DEHP高剂量组的IgE水平与其余各组比较均显著升高（P<0.01）。鼻黏膜组织病理学检查结果显示，除空白组外其余各组小鼠鼻黏膜上皮细胞排列紊乱，细胞间隙增大，纤毛倒伏、脱落、缺失，部分血管扩张和充血，并有大量嗜酸性分泌物。此外，各组小鼠脾脏指数较空白组升高（P<0.05），并且各组血清中白细胞介素4（IL-4）、IL-5、IL-17、转化生长因子β（TGF-β）浓度均升高（P<0.05），而干扰素γ（IFN-γ）浓度下降（P<0.001）。与模型组比较，DEHP高剂量组的IL-4、IL-5、IL-17、TGF-β浓度和IFN-γ浓度下降均有统计学意义（P<0.05），而其余组间差异无统计学意义（P>0.05）。以上结果表明，环境污染物DEHP通过影响Th1/Th2/Th17/Treg细胞因子水平加重AR症状和病理改变，尤其是高剂量300 mg·kg-1的DEHP最为明显，但即使在一般暴露水平30 mg·kg-1和较低剂量3 mg·kg-1也能观察到DEHP对AR的促进作用。

关键词： 电化学免疫传感器   癌胚抗原   层状三金属氢氧化物   导电金属有机框架  

摘要： 本文基于有序介孔碳@导电金属有机框架负载纳米金(CMK-3@Ni3（HITP）2@AuNPS)和二茂铁羧酸@镍钴铜三金属氢氧化物（NiCoCu-LDH@Fc）的电信号放大策略，构建了一种夹心型电化学免疫传感检测癌症标志物癌胚抗原（CEA）。CMK-3@Ni3（HITP）2@AuNPS基底层可特异性捕获癌胚抗原，NiCoCu-LDH@Fc信号层形成氧化还原峰，借助材料的高比表面积、高导电性，为传感器提供了良好的导电基底与信号响应平台。该免疫传感器检出限为0.24 pg/mL，灵敏度和特异性高、重复性好，可应用于癌症的早期诊断。

关键词： Breast cancer   Cancer-associated adipocytes   IL-6   PD-L1   STAT3   miR-497a-5p  

摘要： BACKGROUND:Adipocytes are engaged in the development and progression of breast cancer (BC). Cancer-associated adipocytes (CAAs) are specific adipocytes located at the invasive front of BC that modulate tumor behaviors. This study aimed to investigate the effect of CAA-derived IL-6 in regulating BC progression. METHODS:Human BC specimens and adipocytes co-cultured with BC cells were used to explore the characteristics of CAAs. Adipocytes and 4T1 cells co-implanted in mouse model and tail vein metastasis model were used to explore the effect of CAAs on malignant progression and immunosuppressive tumor microenvironment (TME) of BC in vivo. The functional assays, flow cytometry, ELISA, miRNAs sequencing and dual-luciferase reporter assay were implemented to investigate the role of CAA-derived IL-6 in regulating programmed cell death protein ligand 1 (PD-L1) expression. RESULTS:CAAs were present at the invasive front of BC with a de-differentiated fibroblast phenotype. CAAs enhanced the malignant behaviors of 4T1 BC cells in vitro, and promoted 4T1 tumor growth and lung metastasis with decreased CD8T cells and upregulated Tregs. The IHC results of both human BC specimens and xenografts showed that CAAs could upregulate PD-L1 expression in BC. Besides, CAAs could secrete abundant IL-6 and thus enhanced PD-L1 expression in 4T1 cells and tumors. More importantly, CAA-derived IL-6 could activate STAT3, while STAT3 blockade in CAA-cultured 4T1 cells upregulated miRNA-497a-5p expression and downregulated PD-L1 expression. Dual-luciferase reporter assay indicated that PD-L1 was a direct target of miRNA-497a-5p. CONCLUSIONS:Our study demonstrated that CAAs promoted the malignant behaviors of BC and enhanced immunosuppression in TME. Specifically, CAA-derived IL-6 promoted the PD-L1 expression of BC via STAT3/miR-497a-5p signaling, thereby contributing to BC progression.