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High-throughput synthesis and specificity characterization of natively paired influenza hemagglutinin antibodies with oPool+ display 具有oPool+显示的流感血凝素抗体的高通量合成和特异性表征
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-09-03 DOI: 10.1126/scitranslmed.adt4147
Wenhao O. Ouyang, Huibin Lv, Wenkan Liu, Ruipeng Lei, Zongjun Mou, Tossapol Pholcharee, Logan Talmage, Meixuan Tong, Wei Ji, Yiquan Wang, Katrine E. Dailey, Akshita B. Gopal, Danbi Choi, Madison R. Ardagh, Lucia A. Rodriguez, Jenna J. Guthmiller, Xinghong Dai, Nicholas C. Wu
{"title":"High-throughput synthesis and specificity characterization of natively paired influenza hemagglutinin antibodies with oPool+ display","authors":"Wenhao O. Ouyang,&nbsp;Huibin Lv,&nbsp;Wenkan Liu,&nbsp;Ruipeng Lei,&nbsp;Zongjun Mou,&nbsp;Tossapol Pholcharee,&nbsp;Logan Talmage,&nbsp;Meixuan Tong,&nbsp;Wei Ji,&nbsp;Yiquan Wang,&nbsp;Katrine E. Dailey,&nbsp;Akshita B. Gopal,&nbsp;Danbi Choi,&nbsp;Madison R. Ardagh,&nbsp;Lucia A. Rodriguez,&nbsp;Jenna J. Guthmiller,&nbsp;Xinghong Dai,&nbsp;Nicholas C. Wu","doi":"10.1126/scitranslmed.adt4147","DOIUrl":"10.1126/scitranslmed.adt4147","url":null,"abstract":"<div >Antibody discovery is crucial for developing therapeutics and vaccines and for understanding adaptive immunity. However, the lack of approaches to synthesize antibodies with defined sequences in a high-throughput manner represents a major bottleneck in antibody discovery. Here, we present oPool<sup>+</sup> display, a high-throughput cell-free platform that combined oligo pool synthesis and mRNA display to rapidly construct and characterize hundreds to thousands of natively paired antibodies in parallel. As a proof of concept, we applied oPool<sup>+</sup> display to probe the binding specificity of more than 300 uncommon influenza hemagglutinin-specific antibodies against nine hemagglutinin variants through 16 screens. More than 5000 binding tests were performed in 3 to 5 days of hands-on time with further scaling potential. Follow-up structural and functional analysis of two antibodies revealed the versatility of the human immunoglobulin gene segment D3-3 (<i>IGHD-3-3</i>) in recognizing the hemagglutinin stem. Overall, this study established an experimental platform that not only accelerates antibody characterization but also enables unbiased discovery of recurring molecular signatures among antibodies with the same specificity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer 一种等位基因不可知的突变型kras抑制剂抑制肿瘤维持信号并重新编程胰腺癌的肿瘤免疫
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-09-03 DOI: 10.1126/scitranslmed.adt5511
Kathleen M. McAndrews, Francesca Paradiso, Clint A. Stalnecker, Benson S. Chellakkan, Fredrik I. Thege, David H. Peng, Barbara A. Moreno Diaz, Hikaru Sugimoto, Sarah I. Patel, Krishnan K. Mahadevan, Michelle L. Kirtley, Danielle Wills, Amari M. Sockwell, Andre Luis F. Fonseca, Yunhe Liu, Kimal I. Rajapakshe, Nathaniel G. Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V. Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F. Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E. Deckard, Linghua Wang, Channing J. Der, Christopher Vellano, Paola A. Guerrero, Timothy P. Heffernan, Raghu Kalluri, Anirban Maitra
{"title":"An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer","authors":"Kathleen M. McAndrews,&nbsp;Francesca Paradiso,&nbsp;Clint A. Stalnecker,&nbsp;Benson S. Chellakkan,&nbsp;Fredrik I. Thege,&nbsp;David H. Peng,&nbsp;Barbara A. Moreno Diaz,&nbsp;Hikaru Sugimoto,&nbsp;Sarah I. Patel,&nbsp;Krishnan K. Mahadevan,&nbsp;Michelle L. Kirtley,&nbsp;Danielle Wills,&nbsp;Amari M. Sockwell,&nbsp;Andre Luis F. Fonseca,&nbsp;Yunhe Liu,&nbsp;Kimal I. Rajapakshe,&nbsp;Nathaniel G. Yee,&nbsp;Phuong Thao Tran,&nbsp;Huda Alchikh Omar,&nbsp;Antonio Tedeschi,&nbsp;Fiorella Schischlik-Siegl,&nbsp;Andrew S. Boghossian,&nbsp;Matthew G. Rees,&nbsp;Melissa M. Ronan,&nbsp;Jennifer A. Roth,&nbsp;Dorothea Rudolph,&nbsp;Martin Aichinger,&nbsp;Florian Ebner,&nbsp;Artem V. Artemov,&nbsp;Jesse Lipp,&nbsp;Laura Pisarsky,&nbsp;Valerie Laura Herrmann,&nbsp;John Park,&nbsp;Jörg F. Rippmann,&nbsp;Otmar Schaaf,&nbsp;Vanessa Chandler,&nbsp;Mariah Williams,&nbsp;Charles E. Deckard,&nbsp;Linghua Wang,&nbsp;Channing J. Der,&nbsp;Christopher Vellano,&nbsp;Paola A. Guerrero,&nbsp;Timothy P. Heffernan,&nbsp;Raghu Kalluri,&nbsp;Anirban Maitra","doi":"10.1126/scitranslmed.adt5511","DOIUrl":"10.1126/scitranslmed.adt5511","url":null,"abstract":"<div ><i>KRAS</i> is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small-molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), and syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phosphoproteomic profiling of panKRASi-treated models confirmed RAS pathway inhibition along with up-regulation of LKB1/AMPK (liver kinase B1/AMP-activated protein kinase) targets. In panKRASi-treated immune-replete models, we observed increased intratumoral CD8<sup>+</sup> effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME), enabling responses to immune checkpoint blockade. In the long term, emergence of resistance to panKRASi monotherapy was associated with increased YAP signaling within tumor cells and enhanced expression of immune checkpoints in the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comprehensive analysis of microbial content in whole-genome sequencing samples from The Cancer Genome Atlas project 癌症基因组图谱项目全基因组测序样品中微生物含量的综合分析
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-09-03 DOI: 10.1126/scitranslmed.ads6335
Yuchen Ge, Jennifer Lu, Daniela Puiu, Mahler Revsine, Steven L. Salzberg
{"title":"Comprehensive analysis of microbial content in whole-genome sequencing samples from The Cancer Genome Atlas project","authors":"Yuchen Ge,&nbsp;Jennifer Lu,&nbsp;Daniela Puiu,&nbsp;Mahler Revsine,&nbsp;Steven L. Salzberg","doi":"10.1126/scitranslmed.ads6335","DOIUrl":"10.1126/scitranslmed.ads6335","url":null,"abstract":"<div >In recent years, a growing number of publications have reported the presence of microbial species in human tumors and mixtures of microbes that appear to be highly specific to different cancer types. Our recent reanalysis of data from three cancer types revealed that technical errors have caused erroneous reports of numerous microbial species found in sequencing data from The Cancer Genome Atlas (TCGA) project. Here, we have expanded our analysis to cover all 5734 whole-genome sequencing (WGS) datasets currently available from TCGA, covering 25 distinct types of cancer. We analyzed the microbial content using updated computational methods and databases and compared our results to those from two major recent studies that focused on bacteria, viruses, and fungi in cancer. Our results expand upon and reinforce our recent findings, which show that the presence of microbes is far smaller than had been previously reported and that many species identified in TCGA data might not be present at all. As part of this expanded analysis and to help others avoid being misled by flawed data, we have released a dataset that contains detailed read counts for bacteria, viruses, archaea, and fungi detected in all 5734 TCGA samples, which can serve as a public reference for future investigations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation 通过刺激hsc依赖的细胞外基质降解来解决纤维化
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-08-27 DOI: 10.1126/scitranslmed.ads9470
Sachin Sharma, Vijaya Prathigudupu, Carson Cable, Lia R. Serrano, Srilaxmi Nerella, Alina Chen, Ghmkin Hassan, Johnathon Lakins, Carlos Lizama Valenzuela, Tatsuya Tsukui, Roopa Ramamoorthi, Jae-Jun Kim, Holger Willenbring, Aras N. Mattis, Regan F. Volk, Balyn W. Zaro, Joshua J. Coon, Richard Beresis, William F. DeGrado, Valerie M. Weaver, Stephanie A. Christenson, Hyunil Jo, Jennifer Y. Chen
{"title":"Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation","authors":"Sachin Sharma,&nbsp;Vijaya Prathigudupu,&nbsp;Carson Cable,&nbsp;Lia R. Serrano,&nbsp;Srilaxmi Nerella,&nbsp;Alina Chen,&nbsp;Ghmkin Hassan,&nbsp;Johnathon Lakins,&nbsp;Carlos Lizama Valenzuela,&nbsp;Tatsuya Tsukui,&nbsp;Roopa Ramamoorthi,&nbsp;Jae-Jun Kim,&nbsp;Holger Willenbring,&nbsp;Aras N. Mattis,&nbsp;Regan F. Volk,&nbsp;Balyn W. Zaro,&nbsp;Joshua J. Coon,&nbsp;Richard Beresis,&nbsp;William F. DeGrado,&nbsp;Valerie M. Weaver,&nbsp;Stephanie A. Christenson,&nbsp;Hyunil Jo,&nbsp;Jennifer Y. Chen","doi":"10.1126/scitranslmed.ads9470","DOIUrl":"10.1126/scitranslmed.ads9470","url":null,"abstract":"<div >Tissue fibrosis arises from a critical imbalance between the production and breakdown of extracellular matrix (ECM) components. Whereas current strategies predominantly focus on curbing ECM production, the possibility of promoting ECM degradation to resolve fibrosis remains largely untapped. The role of hepatic stellate cells (HSCs) in ECM degradation is an intriguing area for investigation. We previously demonstrated that inhibiting acid ceramidase (aCDase) increases ceramide in HSCs to ameliorate hepatic fibrosis. Here, we uncover a key signaling pathway that promotes ECM degradation in primary human HSCs, which is dependent upon the activation of protein kinase Cα (PKCα) and the induction of matrix metalloproteinase 1 (MMP-1) through extracellular signal–regulated kinase 1/2 (ERK1/2). Genetic reduction and pharmacological inhibition with a small molecule reduced aCDase activity, leading to increased collagen degradation and hepatic fibrosis resolution in the carbon tetrachloride (CCl<sub>4</sub>) and fructose, palmitate, cholesterol, and trans-fat (FPC) mouse models. Consistently, ceramide signaling correlated with ECM remodeling and degradation in patients with metabolic dysfunction–associated steatotic liver disease. The findings show that ceramide regulates ECM degradation and establish aCDase as a target for therapeutic regression of fibrosis.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 813","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Periadventitial delivery of mesenchymal stem cells improves vascular remodeling and maturation in arteriovenous fistulas 内膜周围移植间充质干细胞可改善动静脉瘘的血管重塑和成熟
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-08-27 DOI: 10.1126/scitranslmed.adp7723
Sreenivasulu Kilari, Randall R. DeMartino, Scott L. Nyberg, Patrick G. Dean, Jill J. Colglazier, Edwin Takahashi, Gaurav Baranwal, Prabh G. Singh, Jamie Kane, Katrin Nitz, Esther Lutgens, John J. Dillon, Roberto I. Vazquez-Padron, Jay Mandrekar, Allan B. Dietz, Debabrata Mukhopadhyay, Sanjay Misra
{"title":"Periadventitial delivery of mesenchymal stem cells improves vascular remodeling and maturation in arteriovenous fistulas","authors":"Sreenivasulu Kilari,&nbsp;Randall R. DeMartino,&nbsp;Scott L. Nyberg,&nbsp;Patrick G. Dean,&nbsp;Jill J. Colglazier,&nbsp;Edwin Takahashi,&nbsp;Gaurav Baranwal,&nbsp;Prabh G. Singh,&nbsp;Jamie Kane,&nbsp;Katrin Nitz,&nbsp;Esther Lutgens,&nbsp;John J. Dillon,&nbsp;Roberto I. Vazquez-Padron,&nbsp;Jay Mandrekar,&nbsp;Allan B. Dietz,&nbsp;Debabrata Mukhopadhyay,&nbsp;Sanjay Misra","doi":"10.1126/scitranslmed.adp7723","DOIUrl":"10.1126/scitranslmed.adp7723","url":null,"abstract":"<div >Worldwide, more than 4 million patients with end-stage kidney disease require hemodialysis through an arteriovenous fistula (AVF). AVFs fail because of venous neointimal hyperplasia (VNH) resulting in venous stenosis formation. A phase 1 randomized trial in patients undergoing upper extremity AVF placement was performed to evaluate the safety and efficacy of autologous adipose–derived mesenchymal stem cells (MSCs) in improving AVF function. The mechanism of action by which MSCs exert their beneficial effects was investigated using AVFs created in mice and pigs treated with allogenic MSCs and xenotransplant using patient MSCs in CD1-<i>Foxn1nu</i> mice. At a median follow-up of 42 months, patients with MSC-treated AVFs had reduced time to maturation with an increase in the vein diameter compared with controls. AVFs treated with allogenic MSCs in mice and pigs had an increase in M2- and M1-like macrophages with a decrease in VNH. Transcriptomic analysis of AVFs treated with allogenic MSCs in mouse and MSC xenotransplants of patients with successful AVFs showed decreased peroxisome proliferator–activated receptor gamma (<i>Ppar</i>γ) and leptin receptor (<i>Lepr</i>) and increased latent transforming growth factor–beta–binding protein 2 (<i>Ltbp2</i>). PPARγ was reduced in CD68 (+) cells from successful AVFs and allogenic MSC-treated mouse AVFs. Venous stenosis and VNH formation were mitigated in AVFs of mice with <i>Ppar</i>γ ablation in immune cells. Conditioned medium from MSCs of responders versus nonresponders had decreased proinflammatory genes, senescence-associated proteins, and monocyte-to-macrophage differentiation induced by phorbol 12-myristate-13-acetate. Periadventitial delivery of MSCs to AVFs promoted positive vascular remodeling through decreased inflammatory responses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 813","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Antigen-Fc fusion therapy reduces severity of a model of pemphigus vulgaris without systemic immunosuppression 抗原fc融合治疗降低了寻常型天疱疮模型的严重程度,而没有全身免疫抑制
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-08-27 DOI: 10.1126/scitranslmed.adk6484
Soheil Tavakolpour, Ali Nili, Leïla A. Munaretto, Chen Kai Huang, Taha Rakhshandehroo, Zachary Kim, Ava E. Knight, Ali Salehi Farid, Mohammed A. Alasharee, Harris Allen, Safak Uslu, Heydar Moravej, Min Cong, Léa Berland, Ester Simkova, Haneyeh Shahbazian, Jennifer E. Rowley, Shreya R. Mantri, Megan H. Noe, Christopher D. Barrett, Ashley Ward, George C. Tsokos, Erin X. Wei, Mohammad Rashidian
{"title":"Antigen-Fc fusion therapy reduces severity of a model of pemphigus vulgaris without systemic immunosuppression","authors":"Soheil Tavakolpour,&nbsp;Ali Nili,&nbsp;Leïla A. Munaretto,&nbsp;Chen Kai Huang,&nbsp;Taha Rakhshandehroo,&nbsp;Zachary Kim,&nbsp;Ava E. Knight,&nbsp;Ali Salehi Farid,&nbsp;Mohammed A. Alasharee,&nbsp;Harris Allen,&nbsp;Safak Uslu,&nbsp;Heydar Moravej,&nbsp;Min Cong,&nbsp;Léa Berland,&nbsp;Ester Simkova,&nbsp;Haneyeh Shahbazian,&nbsp;Jennifer E. Rowley,&nbsp;Shreya R. Mantri,&nbsp;Megan H. Noe,&nbsp;Christopher D. Barrett,&nbsp;Ashley Ward,&nbsp;George C. Tsokos,&nbsp;Erin X. Wei,&nbsp;Mohammad Rashidian","doi":"10.1126/scitranslmed.adk6484","DOIUrl":"10.1126/scitranslmed.adk6484","url":null,"abstract":"<div >Pemphigus vulgaris is a B cell–mediated autoimmune disease characterized by autoantibodies targeting desmoglein-3 (Dsg3), a critical adhesion molecule in epithelial tissues. Current treatments rely on broad immunosuppression, highlighting the need for more targeted therapeutic approaches in pemphigus vulgaris and other autoantibody-driven disorders. We engineered a therapeutic fusion protein consisting of the pathogenic domains of Dsg3 linked to either human immunoglobulin G1 (IgG1) or mouse IgG2a (Dsg3-Fc). In vitro, Dsg3-Fc selectively eliminated Dsg3-autoreactive B cells. In vivo, Dsg3-Fc effectively depleted human B cells expressing patient-derived anti-Dsg3 B cell receptors, even in the presence of circulating autoantibodies. Moreover, Dsg3-Fc inhibited both disease initiation and progression in a polyclonal, active pemphigus vulgaris model in immunocompetent mice. In addition, Dsg3-Fc rapidly neutralized pathogenic autoantibodies without inducing systemic toxicity. These findings demonstrate that targeting pathogenic B cells and neutralizing autoantibodies through autoantigen-Fc fusion proteins may represent a promising therapeutic strategy for pemphigus vulgaris and potentially other autoantibody-mediated diseases without the need for global immunosuppression.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 813","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Immune response and clinical severity are shaped by skin-adapted Staphylococcus aureus in chronically infected patients 慢性感染患者的皮肤适应性金黄色葡萄球菌影响免疫反应和临床严重程度
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-08-27 DOI: 10.1126/scitranslmed.adq7985
Anne Jamet, Xiali Fu, Céline Dietrich, Nathalia Bellon, Messaouda Attailia, Elif Uyar, Mélanie Montabord, Iharilalao Dubail, Khanyisile Kunene, Agnès Ferroni, Laura Polivka, Marion Dupuis, Daniel Euphrasie, Stéphanie Leclerc-Mercier, Nathalie Four, Ines Metatla, Kevin Roger, Joanna Lipecka, Ida Chiara Guerrera, Nicolas Mirouze, Alain Charbit, Mathieu Coureuil, Fabienne Charbit-Henrion, Smail Hadj-Rabia, Julie Steffann, Guillaume Lezmi, Christine Bodemer, Maria Leite-de-Moraes
{"title":"Immune response and clinical severity are shaped by skin-adapted Staphylococcus aureus in chronically infected patients","authors":"Anne Jamet,&nbsp;Xiali Fu,&nbsp;Céline Dietrich,&nbsp;Nathalia Bellon,&nbsp;Messaouda Attailia,&nbsp;Elif Uyar,&nbsp;Mélanie Montabord,&nbsp;Iharilalao Dubail,&nbsp;Khanyisile Kunene,&nbsp;Agnès Ferroni,&nbsp;Laura Polivka,&nbsp;Marion Dupuis,&nbsp;Daniel Euphrasie,&nbsp;Stéphanie Leclerc-Mercier,&nbsp;Nathalie Four,&nbsp;Ines Metatla,&nbsp;Kevin Roger,&nbsp;Joanna Lipecka,&nbsp;Ida Chiara Guerrera,&nbsp;Nicolas Mirouze,&nbsp;Alain Charbit,&nbsp;Mathieu Coureuil,&nbsp;Fabienne Charbit-Henrion,&nbsp;Smail Hadj-Rabia,&nbsp;Julie Steffann,&nbsp;Guillaume Lezmi,&nbsp;Christine Bodemer,&nbsp;Maria Leite-de-Moraes","doi":"10.1126/scitranslmed.adq7985","DOIUrl":"10.1126/scitranslmed.adq7985","url":null,"abstract":"<div >Despite the well-described association of skin lesions with <i>Staphylococcus aureus</i>, the distinct ability of clinical isolates to influence the local and systemic inflammatory response in a patient-specific manner is insufficiently characterized. In this study, we analyzed clinical recessive dystrophic epidermolysis bullosa (RDEB), which is characterized by wounds chronically colonized with <i>S. aureus</i>, to explore the relationship between inflammatory immune response and strain diversity. Children with RDEB (moderate phenotype, <i>n</i> = 5; severe phenotype, <i>n</i> = 10) and controls (<i>n</i> = 18) were enrolled in the study. Profiling of plasma proteins (<i>n</i> = 800), immune cells (<i>n</i> = 30 subsets and cytokine-producing cells), and cytokines (<i>n</i> = 38) identified a specific inflammatory signature in severe disease. Furthermore, patients with severe RDEB presented a high frequency of interleukin-17A+ (IL-17A+) cells among CD4+ and mucosal-associated invariant T (MAIT) lymphocytes. Positive <i>S. aureus</i> cultures from the skin of patients with RDEB allowed whole-genome sequencing of patient strains and assessment of primary keratinocyte immune response upon bacterial challenge. <i>S. aureus</i> secretome and conditioned medium from keratinocytes challenged with <i>S. aureus</i> strains from patients with severe but not from those with moderate RDEB promoted strong activation and a pro–IL-17 response in both CD4+ and MAIT cells. Our findings show that <i>S. aureus</i> strains isolated from patients with severe RDEB induce an IL-17–skewed immune response and pave the way for precision microbiology to explain and predict the highly variable virulence potential of bacterial clinical isolates.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 813","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β–mediated inflammation in mice and humans 饮食饱和脂肪酸促进小鼠和人类肺髓细胞炎性体活化和il -1β介导的炎症
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-08-27 DOI: 10.1126/scitranslmed.adp5653
Sam J. McCright, Olivia Harding, Julia Chini, Nicole DeMarco, Li-Yin Hung, Christopher F. Pastore, Wenyun Lu, Joshua Rabinowitz, Jorge Henao-Mejia, De’Broski R. Herbert, Lisa R. Young, David A. Hill
{"title":"Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β–mediated inflammation in mice and humans","authors":"Sam J. McCright,&nbsp;Olivia Harding,&nbsp;Julia Chini,&nbsp;Nicole DeMarco,&nbsp;Li-Yin Hung,&nbsp;Christopher F. Pastore,&nbsp;Wenyun Lu,&nbsp;Joshua Rabinowitz,&nbsp;Jorge Henao-Mejia,&nbsp;De’Broski R. Herbert,&nbsp;Lisa R. Young,&nbsp;David A. Hill","doi":"10.1126/scitranslmed.adp5653","DOIUrl":"10.1126/scitranslmed.adp5653","url":null,"abstract":"<div >Resident tissue macrophages and monocytes (RTMs) integrate local and systemic signals to coordinate immune cell function at homeostasis and in response to inflammatory stimuli. Obesity-associated metabolic dysfunction drives the development of RTM populations that contribute to disease states in multiple tissues. However, the contribution of specific dietary components to innate immune cell activation and function, as opposed to the direct effects of obesity, is largely unknown. Here, we studied the mechanisms by which high-fat (HF) diets shape lung RTM phenotype and function at steady state and influence responses to inflammatory insults. We found that, during HF diet feeding, lung RTMs accumulate saturated long-chain fatty acids, specifically stearic acid (SA), and demonstrate features of NLRP3 inflammasome priming and activation. In vivo, increased dietary SA was sufficient to cause neutrophil-predominant lung inflammation in the steady state and exacerbate a model of innate airway inflammation, whereas increased dietary oleic acid, the monounsaturated counterpart of SA, was sufficient to reduce inflammasome activation in the steady state and attenuate airway inflammation. Depletion of interleukin-1β (IL-1β) or pharmacologic inhibition of the endonuclease inositol requiring enzyme 1α (IRE1α) protected against SA-induced exacerbated lung inflammation. Last, we identified a population of lung monocytes with hallmarks of HF diet–induced RTM activation that were present in samples from obese humans with asthma. Together, these results identify a class of dietary lipids that regulate lung RTM phenotype and function in the steady state and modulate the severity of inflammation in the lung.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 813","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
NF1-depleted ER+ breast cancers are differentially sensitive to CDK4/6 inhibitors nf1缺失的ER+乳腺癌对CDK4/6抑制剂的敏感性存在差异
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-08-27 DOI: 10.1126/scitranslmed.adq5492
Ze-Yi Zheng, Anran Chen, Eric J. Jaehnig, Meenakshi Anurag, Jonathan T. Lei, Long Feng, Chenwei Wang, Diana Fandino, Purba Singh, Hilda Kennedy, Ghazal Yadav, Craig T. Vollert, Jill Tsai, Xi Chen, Yi Li, Bora Lim, Alastair Thompson, Shunqiang Li, Charles E. Foulds, Bing Zhang, Matthew J. Ellis, Eric C. Chang
{"title":"NF1-depleted ER+ breast cancers are differentially sensitive to CDK4/6 inhibitors","authors":"Ze-Yi Zheng,&nbsp;Anran Chen,&nbsp;Eric J. Jaehnig,&nbsp;Meenakshi Anurag,&nbsp;Jonathan T. Lei,&nbsp;Long Feng,&nbsp;Chenwei Wang,&nbsp;Diana Fandino,&nbsp;Purba Singh,&nbsp;Hilda Kennedy,&nbsp;Ghazal Yadav,&nbsp;Craig T. Vollert,&nbsp;Jill Tsai,&nbsp;Xi Chen,&nbsp;Yi Li,&nbsp;Bora Lim,&nbsp;Alastair Thompson,&nbsp;Shunqiang Li,&nbsp;Charles E. Foulds,&nbsp;Bing Zhang,&nbsp;Matthew J. Ellis,&nbsp;Eric C. Chang","doi":"10.1126/scitranslmed.adq5492","DOIUrl":"10.1126/scitranslmed.adq5492","url":null,"abstract":"<div >Neurofibromin/NF1 is a RAS (rat sarcoma virus) GTPase-activating protein and estrogen receptor (ER) transcriptional corepressor. NF1<sup>low</sup> status, identified by copy number loss or low mRNA/protein expression, is associated with endocrine therapy resistance in ~20% of ER<sup>+</sup>/HER2<sup>−</sup> (human epidermal growth factor receptor 2) early-stage breast cancers. The identification of targeted treatments for NF1<sup>low</sup> ER<sup>+</sup>/HER2<sup>−</sup> breast cancer is therefore a priority. In this study, proteogenomic analysis of ER<sup>+</sup>/HER2<sup>−</sup> breast cancer demonstrated that NF1<sup>low</sup> tumors exhibited elevated cyclin-dependent kinase 4/6 (CDK4/6) activity. In cell lines, <i>NF1</i> deletion had a dual effect on CDK4 activity: first, by promoting ER recruitment to <i>CCND1</i> (cyclin D1), thereby increasing CDK4–cyclin D1 complex formation, and second, by activating C-RAF (rapidly accelerated fibrosarcoma), which drove phosphorylation of the CDK4 activation loop. Preclinical modeling demonstrated that NF1<sup>low</sup> ER<sup>+</sup> cancer cells were more sensitive to fulvestrant combined with a CDK4/6 inhibitor versus fulvestrant alone, with the induction of cell death in vitro and durable tumor regressions in ER<sup>+</sup> NF1<sup>low</sup> patient-derived xenograft models in vivo. Furthermore, NF1<sup>low</sup> ER<sup>+</sup>/HER2<sup>−</sup> tumors were more sensitive to neoadjuvant aromatase inhibitor (AI) plus palbociclib than to neoadjuvant AI alone, as indicated by suppression of mRNA-based proliferation scores. These data are consistent with a model whereby ER and RAS coactivation upon NF1 loss can drive CDK4/6 activity and endocrine therapy resistance but renders NF1<sup>low</sup> ER<sup>+</sup> tumors susceptible to CDK4/6 inhibition. Development of clinical-grade NF1 diagnostics should be prioritized to determine whether NF1<sup>low</sup> ER<sup>+</sup> breast cancers should receive adjusted adjuvant treatment recommendations that reflect increased responsiveness to CDK4/6 inhibition.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 813","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adq5492","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Follicular regulatory T cells promote experimental autoimmune encephalomyelitis by supporting B cell egress from germinal centers 滤泡调节性T细胞通过支持B细胞从生发中心输出促进实验性自身免疫性脑脊髓炎
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-08-27 DOI: 10.1126/scitranslmed.ady1268
Fanny Martinez, Coline Cotineau, Julien Novarino, Cyrielle Bories, Louis Culie, Stephane Rodriguez, Corine Pérals, Simon Lachambre, Valérie Duplan-Eche, Florence Bucciarelli, Béatrice Pignolet, Roland S. Liblau, Laure Michel, Meryem Aloulou, Nicolas Fazilleau
{"title":"Follicular regulatory T cells promote experimental autoimmune encephalomyelitis by supporting B cell egress from germinal centers","authors":"Fanny Martinez,&nbsp;Coline Cotineau,&nbsp;Julien Novarino,&nbsp;Cyrielle Bories,&nbsp;Louis Culie,&nbsp;Stephane Rodriguez,&nbsp;Corine Pérals,&nbsp;Simon Lachambre,&nbsp;Valérie Duplan-Eche,&nbsp;Florence Bucciarelli,&nbsp;Béatrice Pignolet,&nbsp;Roland S. Liblau,&nbsp;Laure Michel,&nbsp;Meryem Aloulou,&nbsp;Nicolas Fazilleau","doi":"10.1126/scitranslmed.ady1268","DOIUrl":"10.1126/scitranslmed.ady1268","url":null,"abstract":"<div >Follicular regulatory T cells (T<sub>fr</sub> cells) constitute a subset of regulatory T cells pivotal to the immune response in germinal centers (GCs) that inhibit autoantibody production. Their role, however, remains ill-defined in autoimmune diseases like multiple sclerosis (MS) and its murine model, experimental autoimmune encephalomyelitis (EAE), which are neuroinflammatory diseases driven by T and B cells. Here, we quantified peripheral blood immune subpopulations in two cohorts of patients with MS and found higher circulating T<sub>fr</sub> cell frequencies in patients in relapse compared with patients in remission. To examine the functional role of T<sub>fr</sub> cells in autoimmune neuroinflammation, we used EAE mouse models and showed that Foxp3<sup>cre/cre</sup>Bcl6<sup>fl/fl</sup> T<sub>fr</sub> cell–deficient mice developed milder EAE than wild-type (WT) mice. Flow cytometry analysis demonstrated that the reduction of encephalomyelitis in T<sub>fr</sub> cell–deficient mice was associated with fewer B cells infiltrating the central nervous system. Coculture experiments showed that B cells isolated from brains of WT mice at the peak of the disease fostered pro-inflammatory cytokine production by myelin oligodendrocyte glycoprotein–specific T cells. We furthermore showed that sphingosine-1-phosphate receptor 2 (S1PR2) expression in GC B cells was up-regulated in T<sub>fr</sub> cell–deficient mice. Treatment with an S1PR2 receptor antagonist abrogated the improved EAE clinical scores in T<sub>fr</sub> cell–deficient mice, and this loss of protection was associated with increased B cell infiltration into the brain and increased pro-inflammatory cytokine production by encephalitogenic T cells. These findings demonstrate that T<sub>fr</sub> cells contribute to autoimmune encephalomyelitis and suggest that their blood frequency reflects MS activity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 813","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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