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Translational research on drug development and biomarker discovery for hepatocellular carcinoma 肝细胞癌药物开发和生物标志物发现的转化研究
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-02-17 DOI: 10.1186/s12929-024-01011-y
Valerie Chew, Chien-Huai Chuang, Chiun Hsu
Translational research plays a key role in drug development and biomarker discovery for hepatocellular carcinoma (HCC). However, unique challenges exist in this field because of the limited availability of human tumor samples from surgery, the lack of homogenous oncogenic driver mutations, and the paucity of adequate experimental models. In this review, we provide insights into these challenges and review recent advancements, with a particular focus on the two main agents currently used as mainstream therapies for HCC: anti-angiogenic agents and immunotherapy. First, we examine the pre-clinical and clinical studies to highlight the challenges of determining the optimal therapeutic combinations with biologically effective dosage for HCC. Second, we discuss biomarker studies focusing on anti-PD1/anti-PD-L1-based combination therapy. Finally, we discuss the progress made in our collective understanding of tumor immunology and in multi-omics analysis technology, which enhance our understanding of the mechanisms underlying immunotherapy, characterize different patient subgroups, and facilitate the development of novel combination approaches to improve treatment efficacy. In summary, this review provides a comprehensive overview of efforts in translational research aiming at advancing our understanding of and improving the treatment of HCC.
转化研究在肝细胞癌(HCC)的药物开发和生物标志物发现方面发挥着关键作用。然而,由于从手术中获得的人类肿瘤样本有限、缺乏同源性致癌驱动突变以及缺乏适当的实验模型,这一领域面临着独特的挑战。在这篇综述中,我们将深入探讨这些挑战并回顾最新进展,尤其关注目前作为 HCC 主流疗法的两种主要药物:抗血管生成药物和免疫疗法。首先,我们考察了临床前和临床研究,以突出确定对 HCC 具有生物有效剂量的最佳治疗组合所面临的挑战。其次,我们讨论了以抗 PD1/ 抗 PD-L1 为基础的联合疗法为重点的生物标志物研究。最后,我们讨论了我们在对肿瘤免疫学的集体理解和多组学分析技术方面取得的进展,这些进展增强了我们对免疫疗法基本机制的理解,描述了不同患者亚群的特征,并促进了新型联合方法的开发以提高疗效。总之,本综述全面概述了转化研究工作,旨在促进我们对 HCC 的了解并改善其治疗。
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引用次数: 0
Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan. 同源重组基因的种系突变与胰腺癌的临床预后:台湾的一项多中心研究。
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-02-13 DOI: 10.1186/s12929-024-01008-7
Siao Muk Cheng, Yung-Yeh Su, Nai-Jung Chiang, Chih-Jung Wang, Ying-Jui Chao, Chien-Jui Huang, Hui-Jen Tsai, Shang-Hung Chen, Chi-Yen Chang, Chia-Rung Tsai, Yi-Jie Li, Chia-Jui Yen, Shih-Chang Chuang, Jeffrey Shu-Ming Chang, Yan-Shen Shan, Daw-Yang Hwang, Li-Tzong Chen

Background: Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population.

Methods: Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy.

Results: Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0-43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7-33.7) versus 9.6 months (95% CI 5.9-17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2-16.9) and 12.6 months (95% CI 10.8-14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis.

Conclusions: Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.

背景:癌症易感基因突变与胰腺导管腺癌(PDAC)有关。然而,在亚洲人群中,PDAC 的遗传状况及其对生存的影响在很大程度上还不为人所知:方法:对 527 例 PDAC 患者的血液样本进行外显子组测序,分析 80 个致癌基因的突变。根据 ACMG 变异分类,诊断出致病和可能致病(P/LP)的种系变异。在接受一线(1L)铂类化疗与无铂化疗的III/IV期患者中,探讨了种系同源重组基因突变(gHRmut,包括BAP1、BRCA1、BRCA2、PALB2、ATM、BLM、BRIP1、CHEK2、NBN、MUTYH、FANCA和FANCC)与治疗结果之间的关联:527 例患者中有 104 例(19.7%)携带 P/LP 基因变异。最常见的变异基因是 BRCA2(3.60%),其次是 ATR(2.66%)和 ATM(1.9%)。中位随访时间为38.3个月(95%置信区间,95% CI 35.0-43.7),中位总生存期(OS)在gHRmut、非HR种系突变或无突变的患者中无显著差异(P = 0.43)。在接受1L联合化疗的320名III/IV期患者中,32人(10%)有gHR突变。其中,与接受无铂化疗的患者相比,接受1L铂类化疗的患者的中位OS明显更长,分别为26.1个月(95% CI 12.7-33.7)对9.6个月(95% CI 5.9-17.6),P = 0.001。然而,在接受1L铂类化疗和无铂化疗的患者中,无gHRmut患者的中位OS分别为14.5个月(95% CI 13.2-16.9)和12.6个月(95% CI 10.8-14.7)(P = 0.22)。在多变量考克斯回归分析中调整了包括年龄、肿瘤分期、表现状态和基线CA 19.9在内的潜在混杂因素后,这些结果是一致的:我们的研究表明,近20%的台湾PDAC患者携带种系P/LP变异。在接受1L铂类化疗的gHRmut患者中观察到更长的生存期,这凸显了在诊断时对所有晚期PDAC患者进行种系检测的重要性。
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引用次数: 0
Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer. Rab37介导PD-1的贩运和膜呈现,以维持肺癌中T细胞的衰竭。
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-02-07 DOI: 10.1186/s12929-024-01009-6
Wan-Ting Kuo, I-Ying Kuo, Hung-Chia Hsieh, Ssu-Ting Wu, Wu-Chou Su, Yi-Ching Wang

Background: Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear.

Methods: Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept.

Results: Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37+/PD-1+/TIM3+/CD8+ tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1+ and TIM3+ in CD8+ T cells exhibiting reduced tumoricidal activity.

Conclusions: Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37high/PD-1high/TIM3high in tumor-infiltrating CD8+ T cells is a biomarker for poor prognosis in lung cancer patients.

背景程序性细胞死亡蛋白 1(PD-1)是一种表达在 T 细胞表面的免疫检查点受体。PD-1 的高表达会导致肿瘤微环境(TME)中的 T 细胞功能障碍。然而,PD-1的胞内转运和质膜表达机制仍不清楚:方法:综合分析肺癌患者的多个数据库,筛选Rab蛋白和潜在的免疫相关信号通路。在 Jurkat T 细胞、脾脏细胞和人类外周血单核细胞(PBMCs)中进行了成像和各种生化检测。Rab37 基因敲除小鼠和肺癌患者标本被用来验证这一概念:在这里,我们发现了由 Rab37 小 GTPase 介导的 PD-1 细胞内转运和质膜呈现的新机制,这种机制可维持 T 细胞衰竭,从而导致患者预后不佳。PD-1以GTP依赖性方式与T细胞的Rab37特异性囊泡共定位,Rab37介导了PD-1的动态贩运和膜呈现。然而,糖基化突变的PD-1会延迟货物招募到Rab37小泡,从而阻碍膜呈现。值得注意的是,与野生型小鼠相比,Rab37基因敲除小鼠肿瘤浸润T细胞的增殖和活性都有所提高。临床上,多重免疫荧光-免疫组化分析表明,Rab37+/PD-1+/TIM3+/CD8+肿瘤浸润T细胞高的患者与肿瘤晚期和总生存率低有关。此外,患者的人 PBMCs 表现出 Rab37 的高表达,这与 CD8+ T 细胞中 PD-1+ 和 TIM3+ 水平的升高呈正相关,表现出杀瘤活性降低:我们的研究结果首次证明了Rab37小GTP酶介导了PD-1的贩运和膜呈递以维持T细胞衰竭,以及Rab37/PD-1轴在肺癌TME的T细胞中的肿瘤促进功能。肿瘤浸润CD8+ T细胞中Rab37高/PD-1高/TIM3高的表达谱是肺癌患者预后不良的生物标志物。
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引用次数: 0
Targeting MDM2 in malignancies is a promising strategy for overcoming resistance to anticancer immunotherapy. 在恶性肿瘤中靶向 MDM2 是克服抗癌免疫疗法耐药性的一种前景广阔的策略。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-01-29 DOI: 10.1186/s12929-024-01004-x
Dantong Sun, Haili Qian, Junling Li, Puyuan Xing

MDM2 has been established as a biomarker indicating poor prognosis for individuals undergoing immune checkpoint inhibitor (ICI) treatment for different malignancies by various pancancer studies. Specifically, patients who have MDM2 amplification are vulnerable to the development of hyperprogressive disease (HPD) following anticancer immunotherapy, resulting in marked deleterious effects on survival rates. The mechanism of MDM2 involves its role as an oncogene during the development of malignancy, and MDM2 can promote both metastasis and tumor cell proliferation, which indirectly leads to disease progression. Moreover, MDM2 is vitally involved in modifying the tumor immune microenvironment (TIME) as well as in influencing immune cells, eventually facilitating immune evasion and tolerance. Encouragingly, various MDM2 inhibitors have exhibited efficacy in relieving the TIME suppression caused by MDM2. These results demonstrate the prospects for breakthroughs in combination therapy using MDM2 inhibitors and anticancer immunotherapy.

通过各种胰腺癌研究,MDM2已被确定为一种生物标志物,表明接受免疫检查点抑制剂(ICI)治疗的不同恶性肿瘤患者预后不佳。具体来说,MDM2扩增的患者在接受抗癌免疫疗法后容易发展为高进展性疾病(HPD),从而对生存率产生明显的有害影响。MDM2 的作用机制涉及其在恶性肿瘤发展过程中作为癌基因的作用,MDM2 可促进转移和肿瘤细胞增殖,从而间接导致疾病进展。此外,MDM2 还参与改变肿瘤免疫微环境(TIME),并影响免疫细胞,最终促进免疫逃避和耐受。令人鼓舞的是,各种 MDM2 抑制剂在缓解 MDM2 导致的 TIME 抑制方面表现出了疗效。这些结果表明,利用 MDM2 抑制剂和抗癌免疫疗法进行联合治疗有望取得突破性进展。
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引用次数: 0
Promising antibacterial efficacy of arenicin peptides against the emerging opportunistic pathogen Mycobacterium abscessus. 菊粉肽对新出现的机会性病原体脓肿分枝杆菌具有良好的抗菌效果。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-01-29 DOI: 10.1186/s12929-024-01007-8
Magali Casanova, Marc Maresca, Isabelle Poncin, Vanessa Point, Hamza Olleik, Céline Boidin-Wichlacz, Aurélie Tasiemski, Kamel Mabrouk, Jean-François Cavalier, Stéphane Canaan

Background: Mycobacterium abscessus, a fast-growing non-tuberculous mycobacterium, is an emerging opportunistic pathogen responsible for chronic bronchopulmonary infections in people with respiratory diseases such as cystic fibrosis (CF). Due to its intrinsic polyresistance to a wide range of antibiotics, most treatments for M. abscessus pulmonary infections are poorly effective. In this context, antimicrobial peptides (AMPs) active against bacterial strains and less prompt to cause resistance, represent a good alternative to conventional antibiotics. Herein, we evaluated the effect of three arenicin isoforms, possessing two or four Cysteines involved in one (Ar-1, Ar-2) or two disulfide bonds (Ar-3), on the in vitro growth of M. abscessus.

Methods: The respective disulfide-free AMPs, were built by replacing the Cysteines with alpha-amino-n-butyric acid (Abu) residue. We evaluated the efficiency of the eight arenicin derivatives through their antimicrobial activity against M. abscessus strains, their cytotoxicity towards human cell lines, and their hemolytic activity on human erythrocytes. The mechanism of action of the Ar-1 peptide was further investigated through membrane permeabilization assay, electron microscopy, lipid insertion assay via surface pressure measurement, and the induction of resistance assay.

Results: Our results demonstrated that Ar-1 was the safest peptide with no toxicity towards human cells and no hemolytic activity, and the most active against M. abscessus growth. Ar-1 acts by insertion into mycobacterial lipids, resulting in a rapid membranolytic effect that kills M. abscessus without induction of resistance.

Conclusion: Overall, the present study emphasized Ar-1 as a potential new alternative to conventional antibiotics in the treatment of CF-associated bacterial infection related to M. abscessus.

背景:脓肿分枝杆菌是一种快速生长的非结核分枝杆菌,是一种新出现的机会性病原体,可导致囊性纤维化(CF)等呼吸系统疾病患者的慢性支气管肺部感染。由于脓肿分枝杆菌对多种抗生素具有固有的多重抗药性,大多数治疗脓肿分枝杆菌肺部感染的方法效果不佳。在这种情况下,抗菌肽(AMPs)对细菌菌株具有活性,且不易产生抗药性,是传统抗生素的良好替代品。在此,我们评估了三种拥有两个或四个半胱氨酸、参与一个(Ar-1、Ar-2)或两个二硫键(Ar-3)的异构体 arenicin 对脓肿霉菌体外生长的影响:方法:通过用α-氨基丁酸(Abu)残基取代半胱氨酸,构建了相应的无二硫键 AMP。我们评估了这八种鸟嘌呤衍生物对脓肿霉菌株的抗菌活性、对人类细胞系的细胞毒性以及对人类红细胞的溶血活性。通过膜渗透试验、电子显微镜、表面压力测量的脂质插入试验以及抗药性诱导试验,进一步研究了 Ar-1 肽的作用机制:结果:我们的研究结果表明,Ar-1 是最安全的多肽,对人体细胞无毒性,无溶血活性,对脓肿霉菌的生长最有效。Ar-1 通过插入分枝杆菌脂质发挥作用,从而产生快速溶膜效应,杀死脓肿霉菌而不诱导抗药性:总之,本研究强调了 Ar-1 在治疗与脓肿霉菌有关的 CF 相关细菌感染方面,是传统抗生素的潜在新替代品。
{"title":"Promising antibacterial efficacy of arenicin peptides against the emerging opportunistic pathogen Mycobacterium abscessus.","authors":"Magali Casanova, Marc Maresca, Isabelle Poncin, Vanessa Point, Hamza Olleik, Céline Boidin-Wichlacz, Aurélie Tasiemski, Kamel Mabrouk, Jean-François Cavalier, Stéphane Canaan","doi":"10.1186/s12929-024-01007-8","DOIUrl":"10.1186/s12929-024-01007-8","url":null,"abstract":"<p><strong>Background: </strong>Mycobacterium abscessus, a fast-growing non-tuberculous mycobacterium, is an emerging opportunistic pathogen responsible for chronic bronchopulmonary infections in people with respiratory diseases such as cystic fibrosis (CF). Due to its intrinsic polyresistance to a wide range of antibiotics, most treatments for M. abscessus pulmonary infections are poorly effective. In this context, antimicrobial peptides (AMPs) active against bacterial strains and less prompt to cause resistance, represent a good alternative to conventional antibiotics. Herein, we evaluated the effect of three arenicin isoforms, possessing two or four Cysteines involved in one (Ar-1, Ar-2) or two disulfide bonds (Ar-3), on the in vitro growth of M. abscessus.</p><p><strong>Methods: </strong>The respective disulfide-free AMPs, were built by replacing the Cysteines with alpha-amino-n-butyric acid (Abu) residue. We evaluated the efficiency of the eight arenicin derivatives through their antimicrobial activity against M. abscessus strains, their cytotoxicity towards human cell lines, and their hemolytic activity on human erythrocytes. The mechanism of action of the Ar-1 peptide was further investigated through membrane permeabilization assay, electron microscopy, lipid insertion assay via surface pressure measurement, and the induction of resistance assay.</p><p><strong>Results: </strong>Our results demonstrated that Ar-1 was the safest peptide with no toxicity towards human cells and no hemolytic activity, and the most active against M. abscessus growth. Ar-1 acts by insertion into mycobacterial lipids, resulting in a rapid membranolytic effect that kills M. abscessus without induction of resistance.</p><p><strong>Conclusion: </strong>Overall, the present study emphasized Ar-1 as a potential new alternative to conventional antibiotics in the treatment of CF-associated bacterial infection related to M. abscessus.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"18"},"PeriodicalIF":9.0,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10823733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
FLT3L-induced virtual memory CD8 T cells engage the immune system against tumors. FLT3L 诱导的虚拟记忆 CD8 T 细胞参与免疫系统对抗肿瘤。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-01-29 DOI: 10.1186/s12929-024-01006-9
Hsin-Fang Tu, Yu-Jui Kung, Ling Lim, Julia Tao, Ming-Hung Hu, Michelle Cheng, Deyin Xing, T C Wu, Chien-Fu Hung

Background: Previous research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells.

Methods: Albumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44high CD8 T cells.

Results: CD44high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44high naïve CD8 T cells revealed FLT3L to induce CD44high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44high CD8 T cells.

Conclusions: These findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.

背景:以往对FMS样酪氨酸激酶3配体(FLT3L)的研究主要集中在它们从骨髓祖细胞生成树突状细胞(DC)的潜力上,而对这些细胞如何影响CD8 T细胞功能的了解有限。在这项研究中,我们进一步研究了FLT3L对CD8 T细胞免疫调节能力的体内作用:方法:白蛋白结合的FLT3L(Alb-FLT3L)被生成并应用于转化医学目的;在此,它被用于治疗幼稚的C57BL/6和OT1小鼠,以进行CD8 T细胞反应分析。我们还利用接种B16ova和E.G7ova小鼠模型进行了采纳性细胞转移,以评估Alb-FLT3L预处理CD8 T细胞对肿瘤进展的影响。为了揭示 Alb-FLT3L 调节的内在机制,我们对 CD44high CD8 T 细胞进行了批量 RNA-seq 分析。我们利用 STAT1 缺陷小鼠来阐明 Alb-FLT3L 在调节 T 细胞中的功能作用。最后,通过抗体阻断一型干扰素信号传导以及质体DCs(pDCs)与幼稚CD8 T细胞体外共培养,确定了pDCs在介导调控CD44high CD8 T细胞中的作用:结果:使用 Alb-FLT3L 的 C57BL/6 小鼠的 CD44high CD8 T 细胞得到了增强。这些 CD8 T 细胞表现出虚拟记忆特征,并具有更强的增殖和有效功能。值得注意的是,将CD44高的天真CD8 T细胞收养性转移到患有B16ova肿瘤的C57BL/6小鼠体内可使肿瘤显著消退。对CD44high天真CD8 T细胞的RNA-seq分析表明,FLT3L以依赖JAK-STAT1信号通路的方式诱导CD44high CD8 T细胞。此外,抗体阻断一型干扰素信号传导限制了 FLT3L 诱导的 CD44 高 CD8 T 细胞的生成,而与来自 FLT3L 处理小鼠的 pDCs 共同培养的幼稚 CD8 T 细胞却能诱导 CD44 表达。这表明 pDCs 在介导 FLT3L 对 CD44 高的 CD8 T 细胞的调控中起着至关重要的作用:这些发现提供了重要的见解,支持了 Alb-FLT3L 作为免疫调节剂在癌症免疫疗法中预处理幼稚 CD8 T 细胞的治疗潜力。
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引用次数: 0
Mechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells. SUMOylation 在健康和疾病中的机制和功能:以免疫细胞为重点的综述。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-01-27 DOI: 10.1186/s12929-024-01003-y
Chien-Hsin Huang, Tsan-Tzu Yang, Kuo-I Lin

SUMOylation, which is a type of post-translational modification that involves covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to target substrates, regulates various important molecular and cellular processes, including transcription, the cell cycle, cell signaling, and DNA synthesis and repair. Newly synthesized SUMO is immature and cleaved by the SUMO-specific protease family, resulting in exposure of the C-terminal Gly-Gly motif to become the mature form. In the presence of ATP, mature SUMO is conjugated with the activating enzyme E1 through the cysteine residue of E1, followed by transfer to the cysteine residue of E2-conjugating enzyme Ubc9 in humans that recognizes and modifies the lysine residue of a substrate protein. E3 SUMO ligases promote SUMOylation. SUMOylation is a reversible modification and mediated by SUMO-specific proteases. Cumulative studies have indicated that SUMOylation affects the functions of protein substrates in various manners, including cellular localization and protein stability. Gene knockout studies in mice have revealed that several SUMO cycling machinery proteins are crucial for the development and differentiation of various cell lineages, including immune cells. Aberrant SUMOylation has been implicated in several types of diseases, including cancers, cardiovascular diseases, and autoimmune diseases. This review summarizes the biochemistry of SUMO modification and the general biological functions of proteins involved in SUMOylation. In particular, this review focuses on the molecular mechanisms by which SUMOylation regulates the development, maturation, and functions of immune cells, including T, B, dendritic, and myeloid cells. This review also discusses the underlying relevance of disruption of SUMO cycling and site-specific interruption of SUMOylation on target proteins in immune cells in diseases, including cancers and infectious diseases.

SUMO酰化是一种翻译后修饰,涉及小泛素样修饰蛋白(SUMO)与目标底物的共价连接,它调控各种重要的分子和细胞过程,包括转录、细胞周期、细胞信号传导以及 DNA 合成和修复。新合成的 SUMO 尚不成熟,会被 SUMO 特异性蛋白酶家族裂解,导致 C 端 Gly-Gly 基序暴露,成为成熟形式。在存在 ATP 的情况下,成熟的 SUMO 通过 E1 的半胱氨酸残基与活化酶 E1 结合,然后转移到 E2 结合酶 Ubc9 的半胱氨酸残基上,后者识别并修饰底物蛋白质的赖氨酸残基。E3 SUMO连接酶促进SUMO化。SUMO 化是一种可逆修饰,由 SUMO 特异性蛋白酶介导。大量研究表明,SUMOylation 会以各种方式影响蛋白质底物的功能,包括细胞定位和蛋白质稳定性。小鼠基因敲除研究发现,一些 SUMO 循环机制蛋白对包括免疫细胞在内的各种细胞系的发育和分化至关重要。异常的 SUMOylation 与多种疾病有关,包括癌症、心血管疾病和自身免疫性疾病。本综述概述了 SUMO 修饰的生物化学以及参与 SUMOylation 的蛋白质的一般生物学功能。本综述尤其关注 SUMOylation 调节免疫细胞(包括 T 细胞、B 细胞、树突状细胞和骨髓细胞)发育、成熟和功能的分子机制。这篇综述还讨论了在包括癌症和传染性疾病在内的各种疾病中,SUMO 循环的中断和免疫细胞中靶蛋白上 SUMO 特异性位点中断的潜在相关性。
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引用次数: 0
Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice. 橙皮素能激活 CISD2,从而减轻老年人角质细胞的衰老,并使小鼠自然衰老的皮肤恢复青春。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-01-23 DOI: 10.1186/s12929-024-01005-w
Zhao-Qing Shen, Cheng-Yen Chang, Chi-Hsiao Yeh, Chung-Kuang Lu, Hao-Chih Hung, Tai-Wen Wang, Kuan-Sheng Wu, Chien-Yi Tung, Ting-Fen Tsai
<p><strong>Background: </strong>CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy.</p><p><strong>Methods: </strong>We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging.</p><p><strong>Results: </strong>Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice.</p><p><strong>Conclusions: </strong>Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperet
背景:CDGSH 含铁硫结构域蛋白 2(CISD2)是一种长寿基因,在哺乳动物中介导健康寿命。CISD2 在衰老过程中下调。此外,在转基因小鼠中,持续高水平的 CISD2 能促进长寿并改善与年龄相关的皮肤表型。在这里,我们利用一种强效的 CISD2 激活剂--橙皮素(hesperetin)将遗传学证据转化为药物应用,它能增强来自老年人的 HEK001 人类角质细胞中 CISD2 的表达。我们还处理了自然衰老的小鼠,以研究该激活剂的抗衰老功效:首先,我们利用细胞平台,即从老年人身上提取的 HEK001 人类角质细胞系,研究了橙皮素对衰老皮肤的生物效应。其次,我们使用了小鼠模型,即 21 个月大的老年小鼠。在后一种情况下,我们研究了橙皮素对紫外线 B(UVB)诱导的光老化和自然老化皮肤的抗衰老功效。此外,为了确定这一过程的潜在机制和生物通路,我们还进行了转录组分析。最后,我们利用 CISD2 基因敲除 HEK001 角质细胞和 Cisd2 基因敲除小鼠来研究 Cisd2 依赖性橙皮素对皮肤老化的影响:结果:有四项发现。首先,在人类皮肤中,CISD2 主要在表皮基底层增殖的角质细胞中表达,此外,CISD2 在暴露于阳光的表皮中下调。其次,在来自老年人的 HEK001 人类角朊细胞中,橙皮素能增强线粒体功能,并通过增加 CISD2 的表达来抵御活性氧诱导的氧化应激;这种增强是 CISD2 依赖性的。此外,橙皮素还能减轻紫外线诱导的损伤,抑制基质金属蛋白酶-1的表达,后者是紫外线诱导角质形成细胞损伤的主要指标。第三,转录组分析表明,橙皮素能调节与线粒体功能、氧化还原平衡、角质形成细胞功能和炎症相关的一系列差异表达基因,从而减轻衰老。耐人寻味的是,橙皮素能激活两个已知的长寿相关调节因子,即 FOXO3a 和 FOXM1,从而抑制衰老相关的分泌表型。最后,在小鼠皮肤中,橙皮素能增强 CISD2 的表达,从而改善紫外线诱导的光老化,而这是通过一种涉及 CISD2 的机制实现的。最引人注目的是,在小鼠21个月大时开始使用橙皮素并持续5个月的晚期治疗,能够延缓皮肤衰老并使自然衰老的皮肤恢复青春:我们的研究结果表明,在小鼠晚期使用橙皮甙药理疗法提高 CISD2 的表达是一种可行的方法,可有效缓解内在和外在的皮肤衰老,而且橙皮甙可作为一种功能性食品或护肤品来抗击皮肤衰老。
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引用次数: 0
Modelling the complex nature of the tumor microenvironment: 3D tumor spheroids as an evolving tool. 模拟肿瘤微环境的复杂性:三维肿瘤球体是一种不断发展的工具。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-01-23 DOI: 10.1186/s12929-024-00997-9
Daniel B Rodrigues, Rui L Reis, Rogério P Pirraco

Cancer remains a serious burden in society and while the pace in the development of novel and more effective therapeutics is increasing, testing platforms that faithfully mimic the tumor microenvironment are lacking. With a clear shift from animal models to more complex in vitro 3D systems, spheroids emerge as strong options in this regard. Years of development have allowed spheroid-based models to better reproduce the biomechanical cues that are observed in the tumor-associated extracellular matrix (ECM) and cellular interactions that occur in both a cell-cell and cell-ECM manner. Here, we summarize some of the key cellular interactions that drive tumor development, progression and invasion, and how successfully are these interactions recapitulated in 3D spheroid models currently in use in the field. We finish by speculating on future advancements in the field and on how these can shape the relevance of spherical 3D models for tumor modelling.

癌症仍然是社会的沉重负担,虽然新型和更有效疗法的开发速度正在加快,但却缺乏能忠实模拟肿瘤微环境的测试平台。随着动物模型向更复杂的体外三维系统的明显转变,球形体成为这方面的有力选择。经过多年的发展,球基模型已能更好地再现肿瘤相关细胞外基质(ECM)中观察到的生物力学线索,以及以细胞-细胞和细胞-ECM方式发生的细胞相互作用。在此,我们总结了推动肿瘤发生、发展和侵袭的一些关键细胞相互作用,以及目前该领域使用的三维球形模型是如何成功再现这些相互作用的。最后,我们将对该领域的未来进展以及这些进展将如何塑造球形三维模型与肿瘤建模的相关性进行推测。
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引用次数: 0
TEM1/endosialin/CD248 promotes pathologic scarring and TGF-β activity through its receptor stability in dermal fibroblasts. TEM1/endosialin/CD248 通过其在真皮成纤维细胞中的受体稳定性促进病理性瘢痕形成和 TGF-β 活性。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-01-23 DOI: 10.1186/s12929-024-01001-0
Yi-Kai Hong, Yu-Chen Lin, Tsung-Lin Cheng, Chao-Han Lai, Yi-Han Chang, Yu-Lun Huang, Chia-Yi Hung, Chen-Han Wu, Kuo-Shu Hung, Ya-Chu Ku, Yen-Ting Ho, Ming-Jer Tang, Shu-Wha Lin, Guey-Yueh Shi, John A McGrath, Hua-Lin Wu, Chao-Kai Hsu

Background: Pathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars.

Methods: To investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-β-mediated responses in pathologic scars.

Results: The levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-β1 signaling through binding with and stabilizing TGF-β receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids.

Conclusions: Our data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-β signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars.

背景:病理性疤痕(包括瘢痕疙瘩和增生性疤痕)是一种常见的夸张性皮肤疤痕,难以有效预防或治疗。此外,人们对病理性疤痕的病理生物学仍然知之甚少。我们的目的是研究 TEM1(又称内糖蛋白或 CD248)(一种糖基化的 I 型跨膜蛋白)对病理性疤痕发展的影响:为了研究 TEM1 的表达,我们采用了免疫荧光染色、Western 印迹和单细胞 RNA 序列(scRNA-seq)技术。我们进行了体外细胞培养实验和体内拉伸诱导疤痕小鼠模型,研究 TEM1 参与 TGF-β 介导的病理疤痕反应:结果:与正常皮肤相比,增生性疤痕和瘢痕疙瘩中蛋白质 TEM1 的水平都有所升高。对scRNA-seq数据集的重新分析表明,瘢痕疙瘩和增生性疤痕成纤维细胞的一个主要坏死亚群大量表达TEM1,在成纤维细胞活化过程中表达量增加。TEM1 通过与 TGF-β 受体结合并稳定 TGF-β 受体,增强 TGF-β1 信号传导,从而促进人真皮成纤维细胞的活化、增殖和 ECM 生成。在拉伸诱发病理性瘢痕的小鼠模型中,Tem1 的全面缺失明显减少了瘢痕中 ECM 的合成量和炎症。瘤内注射针对 TEM1 的人源化 IgG 单克隆抗体 Ontuxizumab 能显著减少瘢痕疙瘩的大小和胶原密度:我们的数据表明,TEM1在病理性瘢痕形成中发挥作用,其对TGF-β信号传导的协同作用有助于真皮成纤维细胞的活化。以TEM1为靶点可能是降低病理性疤痕发病率的一种新型治疗方法。
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引用次数: 0
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