Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1. Kdm6a is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of Kdm6a in microglia in MS because this cell type plays a key role in the neuropathology of MS. Kdm6a was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of Kdm6a in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of Kdm6a in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A’s histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of KDM6A in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that KDM6A might contribute to sex differences in susceptibility to MS.
{"title":"Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles","authors":"Yuichiro Itoh, Noriko Itoh, Sophia Wendin, Nadya Higgins, Rhonda R. Voskuhl","doi":"10.1126/scitranslmed.adq3401","DOIUrl":"10.1126/scitranslmed.adq3401","url":null,"abstract":"<div >Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1. <i>Kdm6a</i> is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of <i>Kdm6a</i> in microglia in MS because this cell type plays a key role in the neuropathology of MS. <i>Kdm6a</i> was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of <i>Kdm6a</i> in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of <i>Kdm6a</i> in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A’s histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of <i>KDM6A</i> in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that <i>KDM6A</i> might contribute to sex differences in susceptibility to MS.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295132","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}
Pub Date : 2025-10-15DOI: 10.1126/scitranslmed.adu0351
Junping Yin, Melanie Eichler, Darius P. Schaub, Nariaki Asada, Jonas Engesser, Clivia Lisowski, Hans-Joachim Paust, Christina Katharina Weisheit, Jian Li, Daniela Klaus, Natalio Garbi, Sibylle von Vietinghoff, Christian F. Krebs, Ulf Panzer, Christian Kurts
Glucocorticoids are widely used to treat autoimmune diseases like crescentic glomerulonephritis (cGN), but their immunosuppressive functions are not fully understood. Here, we generated a single immune cell sequencing atlas at different stages of experimental cGN. We identified a proinflammatory neutrophil subset as important for disease progression and as a glucocorticoid target. Such neutrophils produced proinflammatory cytokines known to drive cGN and expressed Siglec-F and decoy tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (dcTRAIL-R1) in mice and SIGLEC8 in humans. Depleting such neutrophils attenuated disease in mice, whereas their adoptive transfer aggravated disease. They differentiated within the inflamed kidney in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by clonally expanded CD4+ T helper 17 (TH17) cells and persisted locally longer than normal neutrophils. Glucocorticoids decreased intrarenal numbers of TH17 cells and down-regulated GM-CSF receptor expression by neutrophils and reduced their cytokine production. Selective genetic reduction of glucocorticoid receptor expression in neutrophils reenabled their in vivo differentiation during glucocorticoid therapy and aggravated cGN. Low glucocorticoid doses were sufficient to prevent intrarenal neutrophil differentiation in mice, if applied repetitively, even without an initial high-dose steroid pulse. Spatial sequencing of kidney biopsies, especially from patients with high disease activity, uncovered similar neutrophils in intrarenal inflammatory niches, and their abundance was lower after repetitive low-dose glucocorticoid application. These findings identify proinflammatory neutrophils as progression drivers in cGN and suggest that low-dose glucocorticoid therapy may be sufficient to suppress them.
糖皮质激素被广泛用于治疗月牙性肾小球肾炎（cGN）等自身免疫性疾病，但其免疫抑制功能尚不完全清楚。在这里，我们在实验cGN的不同阶段生成了单个免疫细胞测序图谱。我们确定了促炎中性粒细胞亚群对疾病进展和糖皮质激素靶标很重要。这些中性粒细胞产生促炎细胞因子，已知可驱动cGN，并在小鼠中表达siglecf和诱饵肿瘤坏死因子相关凋亡诱导配体受体1 (dcTRAIL-R1)，在人类中表达SIGLEC8。消耗这些中性粒细胞可以减轻小鼠的疾病，而它们的过继转移则会加重疾病。它们在炎症肾脏内对粒细胞-巨噬细胞集落刺激因子（GM-CSF）的反应进行分化，该因子是由克隆扩增的CD4 + T辅助17 （T H 17）细胞分泌的，并且比正常中性粒细胞在局部持续的时间更长。糖皮质激素减少肾内ht17细胞数量，下调中性粒细胞GM-CSF受体的表达，减少其细胞因子的产生。中性粒细胞中糖皮质激素受体表达的选择性遗传减少在糖皮质激素治疗和cGN加重期间重新激活了它们的体内分化。低剂量的糖皮质激素足以防止小鼠肾内中性粒细胞分化，如果重复使用，即使没有初始高剂量的类固醇脉冲。肾脏活检的空间测序，特别是来自疾病活动性高的患者，发现肾内炎症龛中有类似的中性粒细胞，并且在重复使用低剂量糖皮质激素后，它们的丰度较低。这些发现确定促炎中性粒细胞是cGN的进展驱动因素，并提示低剂量糖皮质激素治疗可能足以抑制它们。
{"title":"Low-dose glucocorticoids attenuate crescentic glomerulonephritis by inhibiting the local differentiation of proinflammatory neutrophils","authors":"Junping Yin, Melanie Eichler, Darius P. Schaub, Nariaki Asada, Jonas Engesser, Clivia Lisowski, Hans-Joachim Paust, Christina Katharina Weisheit, Jian Li, Daniela Klaus, Natalio Garbi, Sibylle von Vietinghoff, Christian F. Krebs, Ulf Panzer, Christian Kurts","doi":"10.1126/scitranslmed.adu0351","DOIUrl":"10.1126/scitranslmed.adu0351","url":null,"abstract":"<div >Glucocorticoids are widely used to treat autoimmune diseases like crescentic glomerulonephritis (cGN), but their immunosuppressive functions are not fully understood. Here, we generated a single immune cell sequencing atlas at different stages of experimental cGN. We identified a proinflammatory neutrophil subset as important for disease progression and as a glucocorticoid target. Such neutrophils produced proinflammatory cytokines known to drive cGN and expressed Siglec-F and decoy tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (dcTRAIL-R1) in mice and SIGLEC8 in humans. Depleting such neutrophils attenuated disease in mice, whereas their adoptive transfer aggravated disease. They differentiated within the inflamed kidney in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by clonally expanded CD4<sup>+</sup> T helper 17 (T<sub>H</sub>17) cells and persisted locally longer than normal neutrophils. Glucocorticoids decreased intrarenal numbers of T<sub>H</sub>17 cells and down-regulated GM-CSF receptor expression by neutrophils and reduced their cytokine production. Selective genetic reduction of glucocorticoid receptor expression in neutrophils reenabled their in vivo differentiation during glucocorticoid therapy and aggravated cGN. Low glucocorticoid doses were sufficient to prevent intrarenal neutrophil differentiation in mice, if applied repetitively, even without an initial high-dose steroid pulse. Spatial sequencing of kidney biopsies, especially from patients with high disease activity, uncovered similar neutrophils in intrarenal inflammatory niches, and their abundance was lower after repetitive low-dose glucocorticoid application. These findings identify proinflammatory neutrophils as progression drivers in cGN and suggest that low-dose glucocorticoid therapy may be sufficient to suppress them.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295131","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}
The extracellular matrix (ECM) plays a crucial role in supporting metastasis in solid malignancies, yet effective ECM-targeted therapies remain scarce. Here, we introduce a dual-targeting strategy to combat melanoma by leveraging bispecific agents that disrupt key ECM and tumor-associated pathways. Building on the inhibitory properties of lysyl oxidase–propeptide (LOX-PP), we engineered biselective decoys that simultaneously target the collagen cross-linking enzyme LOX and heat shock protein 70 (HSP70), both of which are up-regulated during melanoma progression in both human and mouse models. This dual-targeting strategy offers a new avenue for disrupting ECM-driven tumor progression and enhancing therapeutic efficacy. Administered to mouse models of melanoma, the decoys reduced tumor burden and circulating melanoma cells by inhibiting proliferation and lung metastasis. Mechanistically, the decoys suppressed cancer-supporting ECM organization, inhibited ECM-remodeling pathways and associated enzymes, and reshaped the tumor immune microenvironment. The treatment modulated immune responses by enhancing neutrophil, B cell, and CD8+ T cell infiltration. In combination with immune check point inhibitor, the decoys further promoted melanoma killing by CD8+ T cells. The decoys efficiently bound multiple human tumors expressing LOX+/HSP70+ ex vivo. These findings highlight the potential of dual inhibition as a potential strategy for remodeling melanoma and other tumor microenvironments and enhancing immunotherapy efficacy.
{"title":"Biselective remodeling of the melanoma tumor microenvironment prevents metastasis and enhances immune activation in mouse models","authors":"Nikolaos A. Afratis, Shivang Parikh, Idan Adir, Roma Parikh, Inna Solomonov, Orit Kollet, Sivan Gelb, Yuval Sade, Hananya Vaknine, Valentina Zemser-Werner, Ronen Brener, Eran Nizri, Dov Hershkovitz, Sylvie Ricard-Blum, Carmit Levy, Irit Sagi","doi":"10.1126/scitranslmed.adp3236","DOIUrl":"10.1126/scitranslmed.adp3236","url":null,"abstract":"<div >The extracellular matrix (ECM) plays a crucial role in supporting metastasis in solid malignancies, yet effective ECM-targeted therapies remain scarce. Here, we introduce a dual-targeting strategy to combat melanoma by leveraging bispecific agents that disrupt key ECM and tumor-associated pathways. Building on the inhibitory properties of lysyl oxidase–propeptide (LOX-PP), we engineered biselective decoys that simultaneously target the collagen cross-linking enzyme LOX and heat shock protein 70 (HSP70), both of which are up-regulated during melanoma progression in both human and mouse models. This dual-targeting strategy offers a new avenue for disrupting ECM-driven tumor progression and enhancing therapeutic efficacy. Administered to mouse models of melanoma, the decoys reduced tumor burden and circulating melanoma cells by inhibiting proliferation and lung metastasis. Mechanistically, the decoys suppressed cancer-supporting ECM organization, inhibited ECM-remodeling pathways and associated enzymes, and reshaped the tumor immune microenvironment. The treatment modulated immune responses by enhancing neutrophil, B cell, and CD8<sup>+</sup> T cell infiltration. In combination with immune check point inhibitor, the decoys further promoted melanoma killing by CD8<sup>+</sup> T cells. The decoys efficiently bound multiple human tumors expressing LOX<sup>+</sup>/HSP70<sup>+</sup> ex vivo. These findings highlight the potential of dual inhibition as a potential strategy for remodeling melanoma and other tumor microenvironments and enhancing immunotherapy efficacy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295828","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}
Pub Date : 2025-10-15DOI: 10.1126/scitranslmed.adu2085
Grace G. Hendricks, Lilit Grigoryan, Mary Jane Navarro, Nicholas J. Catanzaro, Miranda L. Hubbard, John M. Powers, Melissa Mattocks, Catherine Treichel, Alexandra C. Walls, Jimin Lee, Daniel Ellis, Jing Yang (John) Wang, Suna Cheng, Marcos C. Miranda, Adian Valdez, Cara W. Chao, Sidney Chan, Christine Men, Max R. Johnson, Samantha K. Zepeda, Sebastian Ols, Harold Hui, Sheng-Yang Wu, Victor Lujan, Hiromi Muramatsu, Paulo J.C. Lin, Molly M.H. Sung, Ying K. Tam, Elizabeth M. Leaf, Norbert Pardi, Ralph S. Baric, Bali Pulendran, David Veesler, Alexandra Schäfer, Neil P. King
Messenger RNA (mRNA) vaccines and computationally designed protein nanoparticle vaccines were both clinically derisked and licensed for the first time during the coronavirus disease 2019 (COVID-19) pandemic. These vaccine modalities have complementary immunological benefits that provide strong motivation for their combination. Here, we demonstrate proof of concept for genetic delivery of computationally designed protein nanoparticle immunogens. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model system, we genetically fused a stabilized variant of the Wuhan-Hu-1 spike protein receptor binding domain (RBD) to a protein nanoparticle we previously designed for optimal secretion from human cells. Upon secretion, the nanoparticle formed monodisperse and antigenically intact assemblies displaying 60 copies of the RBD in an immunogenic array. Compared with mRNA vaccines encoding membrane-anchored spike protein and a secreted RBD trimer, an mRNA vaccine encoding the RBD nanoparticle elicited 5- to 28-fold higher titers of neutralizing antibodies in mice. In addition, the “mRNA-launched” RBD nanoparticle vaccine induced higher frequencies of antigen-specific CD8 T cells than the same immunogen delivered as adjuvanted protein and protected mice from either Wuhan-Hu-1 or Omicron BA.5 challenge. These results establish that delivering computationally designed protein nanoparticle immunogens through mRNA can combine the benefits of both vaccine modalities. More broadly, our data highlight the utility of computational protein design in genetic vaccination strategies.
在2019年冠状病毒病（COVID-19）大流行期间，信使RNA （mRNA）疫苗和计算设计的蛋白质纳米颗粒疫苗在临床上都是无风险的，并首次获得许可。这些疫苗形式具有互补的免疫益处，为它们的组合提供了强有力的动力。在这里，我们展示了计算设计的蛋白质纳米粒子免疫原的遗传传递的概念证明。以严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）为模型系统，我们将武汉-胡-1刺突蛋白受体结合域（RBD）的稳定变体遗传融合到我们之前设计的用于人类细胞最佳分泌的蛋白质纳米颗粒上。分泌后，纳米颗粒形成单分散和抗原性完整的组装，在免疫原阵列中显示60个RBD拷贝。与编码膜锚定刺突蛋白和分泌的RBD三聚体的mRNA疫苗相比，编码RBD纳米颗粒的mRNA疫苗在小鼠中引发的中和抗体滴度高出5至28倍。此外，“mrna启动”的RBD纳米颗粒疫苗比作为佐剂蛋白递送的相同免疫原诱导抗原特异性CD8 T细胞的频率更高，并保护小鼠免受武汉- hu -1或Omicron BA.5的攻击。这些结果表明，通过mRNA传递计算设计的蛋白质纳米颗粒免疫原可以结合两种疫苗模式的益处。更广泛地说，我们的数据强调了计算蛋白设计在遗传疫苗接种策略中的效用。
{"title":"Computationally designed mRNA-launched protein nanoparticle immunogens elicit protective antibody and T cell responses in mice","authors":"Grace G. Hendricks, Lilit Grigoryan, Mary Jane Navarro, Nicholas J. Catanzaro, Miranda L. Hubbard, John M. Powers, Melissa Mattocks, Catherine Treichel, Alexandra C. Walls, Jimin Lee, Daniel Ellis, Jing Yang (John) Wang, Suna Cheng, Marcos C. Miranda, Adian Valdez, Cara W. Chao, Sidney Chan, Christine Men, Max R. Johnson, Samantha K. Zepeda, Sebastian Ols, Harold Hui, Sheng-Yang Wu, Victor Lujan, Hiromi Muramatsu, Paulo J.C. Lin, Molly M.H. Sung, Ying K. Tam, Elizabeth M. Leaf, Norbert Pardi, Ralph S. Baric, Bali Pulendran, David Veesler, Alexandra Schäfer, Neil P. King","doi":"10.1126/scitranslmed.adu2085","DOIUrl":"10.1126/scitranslmed.adu2085","url":null,"abstract":"<div >Messenger RNA (mRNA) vaccines and computationally designed protein nanoparticle vaccines were both clinically derisked and licensed for the first time during the coronavirus disease 2019 (COVID-19) pandemic. These vaccine modalities have complementary immunological benefits that provide strong motivation for their combination. Here, we demonstrate proof of concept for genetic delivery of computationally designed protein nanoparticle immunogens. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model system, we genetically fused a stabilized variant of the Wuhan-Hu-1 spike protein receptor binding domain (RBD) to a protein nanoparticle we previously designed for optimal secretion from human cells. Upon secretion, the nanoparticle formed monodisperse and antigenically intact assemblies displaying 60 copies of the RBD in an immunogenic array. Compared with mRNA vaccines encoding membrane-anchored spike protein and a secreted RBD trimer, an mRNA vaccine encoding the RBD nanoparticle elicited 5- to 28-fold higher titers of neutralizing antibodies in mice. In addition, the “mRNA-launched” RBD nanoparticle vaccine induced higher frequencies of antigen-specific CD8 T cells than the same immunogen delivered as adjuvanted protein and protected mice from either Wuhan-Hu-1 or Omicron BA.5 challenge. These results establish that delivering computationally designed protein nanoparticle immunogens through mRNA can combine the benefits of both vaccine modalities. More broadly, our data highlight the utility of computational protein design in genetic vaccination strategies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 820","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295129","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}
Pub Date : 2025-10-08DOI: 10.1126/scitranslmed.adv2881
Alexander L. Ling, Jennifer Gantchev, Michael C. Prabhu, Sreyashi Basu, Ryuhjin Ahn, Alicia D’Souza, Nafisa Masud, Anna Ball, Odysseas Nikas, Genaro R. Villa, Michael S. Regan, Gerard Baquer, Georges Ayoub, Charles A. Whittaker, Zaki Abou-Mrad, Andres Santos, Charles P. Couturier, Dina Elharouni, Jayne Vogelzang, Kenny K. H. Yu, Hong Chen, Zhong He, Wen Jiang, Calixto Hope Lucas, Haley E. Sax, Frederick F. Lang, Vinay K. Puduvalli, Viviane Tabar, Cameron W. Brennan, Adrienne Boire, Matthias Holdhoff, Chetan Bettegowda, Michael Cima, Isaac H. Solomon, Ying Yuan, Paul P. Tak, Accelerating GBM Therapies TeamLab, Padmanee Sharma, Forest M. White, Keith L. Ligon, Nathalie Y.R. Agar, David A. Reardon, Giacomo Oliveira, E. Antonio Chiocca
Recurrent glioblastoma (rGBM) remains incurable. One barrier to the development of effective rGBM therapies is the difficulty in collecting posttreatment tumor tissue. Serial multiomic assays from longitudinal rGBM biopsies may uncover tumor responses to a treatment. Here, we obtained 97 serial rGBM biopsy cores over 4 months from the first two patients participating in a clinical trial of repeated intratumoral dosing of the immunotherapeutic agent CAN-3110. Multiomic analysis of the biopsy cores revealed therapeutic effects, including longitudinal and spatial reshaping of the rGBM’s microenvironment, expansion of new T cell tissue-resident effector memory clonotypes against CAN-3110 epitopes and other undetermined antigens, and expression of human leukocyte antigen (HLA)–presented immunopeptides, including cancer testis antigens. Moreover, serial integrated multimodal analyses provided evidence of therapeutic responses to CAN-3110 despite traditional magnetic resonance imaging indicating progression. Clinically, the two treated patients achieved a pathologic response or stable clinical disease, respectively. These results show the value of longitudinal tissue sampling to understand rGBM’s evolution during administration of an investigational therapy.
{"title":"Serial multiomics uncovers anti-glioblastoma responses not evident by routine clinical analyses","authors":"Alexander L. Ling, Jennifer Gantchev, Michael C. Prabhu, Sreyashi Basu, Ryuhjin Ahn, Alicia D’Souza, Nafisa Masud, Anna Ball, Odysseas Nikas, Genaro R. Villa, Michael S. Regan, Gerard Baquer, Georges Ayoub, Charles A. Whittaker, Zaki Abou-Mrad, Andres Santos, Charles P. Couturier, Dina Elharouni, Jayne Vogelzang, Kenny K. H. Yu, Hong Chen, Zhong He, Wen Jiang, Calixto Hope Lucas, Haley E. Sax, Frederick F. Lang, Vinay K. Puduvalli, Viviane Tabar, Cameron W. Brennan, Adrienne Boire, Matthias Holdhoff, Chetan Bettegowda, Michael Cima, Isaac H. Solomon, Ying Yuan, Paul P. Tak, Accelerating GBM Therapies TeamLab, Padmanee Sharma, Forest M. White, Keith L. Ligon, Nathalie Y.R. Agar, David A. Reardon, Giacomo Oliveira, E. Antonio Chiocca","doi":"10.1126/scitranslmed.adv2881","DOIUrl":"10.1126/scitranslmed.adv2881","url":null,"abstract":"<div >Recurrent glioblastoma (rGBM) remains incurable. One barrier to the development of effective rGBM therapies is the difficulty in collecting posttreatment tumor tissue. Serial multiomic assays from longitudinal rGBM biopsies may uncover tumor responses to a treatment. Here, we obtained 97 serial rGBM biopsy cores over 4 months from the first two patients participating in a clinical trial of repeated intratumoral dosing of the immunotherapeutic agent CAN-3110. Multiomic analysis of the biopsy cores revealed therapeutic effects, including longitudinal and spatial reshaping of the rGBM’s microenvironment, expansion of new T cell tissue-resident effector memory clonotypes against CAN-3110 epitopes and other undetermined antigens, and expression of human leukocyte antigen (HLA)–presented immunopeptides, including cancer testis antigens. Moreover, serial integrated multimodal analyses provided evidence of therapeutic responses to CAN-3110 despite traditional magnetic resonance imaging indicating progression. Clinically, the two treated patients achieved a pathologic response or stable clinical disease, respectively. These results show the value of longitudinal tissue sampling to understand rGBM’s evolution during administration of an investigational therapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243244","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}
Pub Date : 2025-10-08DOI: 10.1126/scitranslmed.adn3179
Lucía Pascual-Antón, Pilar Sandoval, Henar Tomero-Sanz, Michela Terri, Raffaele Strippoli, Íñigo García-Sanz, Cristina Marín-Campos, Miguel Ángel del Pozo, Maryam Obaid, Valentina Garcia, Peter Alex Smith, Timothy J. Keane, Molly M. Stevens, Manuel López-Cabrera
Tissue trauma initiates inflammation that can lead to fibrotic complications such as postoperative peritoneal adhesions, which contribute to chronic pain, infertility, and bowel obstruction. Despite their prevalence and impact, effective interventions to prevent adhesion formation remain limited. In this study, we evaluated a sprayable extracellular matrix (ECM) hydrogel as a barrier to protect healing tissues and reduce adhesion formation after abdominal surgery. In both mouse and rabbit models of colorectal and gynecologic procedures, ECM hydrogel application resulted in a substantial reduction in adhesion severity. Mechanistic studies demonstrated that the hydrogel promotes preservation or restoration of the mesothelial lining while modulating early local inflammation. Treated tissues exhibited reduced expression of inflammatory cytokines, including IL-1β, and maintained an intact mesothelial surface with fewer activated myofibroblasts compared with synthetic hydrogel and controls. Immunohistochemical analysis, transcriptomic profiling of mesothelial cells, and in vitro mechanical stretch experiments revealed that the ECM hydrogel mitigates mesothelial-to-mesenchymal transition. These findings suggest that the hydrogel not only provides a physical barrier but also serves as a biological modulator, shielding tissue from mechanical and inflammatory cues that drive adhesion formation. Overall, this study identifies a dual-function, biologically active ECM hydrogel capable of protecting healing tissues and reducing adhesion development in preclinical surgical models. These results support the potential of ECM hydrogel as a clinically translatable, biocompatible strategy for improving postsurgical healing outcomes and reducing adhesion-related complications.
{"title":"Sprayable extracellular matrix hydrogel reduces postoperative adhesion formation and protects healing tissues in preclinical models","authors":"Lucía Pascual-Antón, Pilar Sandoval, Henar Tomero-Sanz, Michela Terri, Raffaele Strippoli, Íñigo García-Sanz, Cristina Marín-Campos, Miguel Ángel del Pozo, Maryam Obaid, Valentina Garcia, Peter Alex Smith, Timothy J. Keane, Molly M. Stevens, Manuel López-Cabrera","doi":"10.1126/scitranslmed.adn3179","DOIUrl":"10.1126/scitranslmed.adn3179","url":null,"abstract":"<div >Tissue trauma initiates inflammation that can lead to fibrotic complications such as postoperative peritoneal adhesions, which contribute to chronic pain, infertility, and bowel obstruction. Despite their prevalence and impact, effective interventions to prevent adhesion formation remain limited. In this study, we evaluated a sprayable extracellular matrix (ECM) hydrogel as a barrier to protect healing tissues and reduce adhesion formation after abdominal surgery. In both mouse and rabbit models of colorectal and gynecologic procedures, ECM hydrogel application resulted in a substantial reduction in adhesion severity. Mechanistic studies demonstrated that the hydrogel promotes preservation or restoration of the mesothelial lining while modulating early local inflammation. Treated tissues exhibited reduced expression of inflammatory cytokines, including IL-1β, and maintained an intact mesothelial surface with fewer activated myofibroblasts compared with synthetic hydrogel and controls. Immunohistochemical analysis, transcriptomic profiling of mesothelial cells, and in vitro mechanical stretch experiments revealed that the ECM hydrogel mitigates mesothelial-to-mesenchymal transition. These findings suggest that the hydrogel not only provides a physical barrier but also serves as a biological modulator, shielding tissue from mechanical and inflammatory cues that drive adhesion formation. Overall, this study identifies a dual-function, biologically active ECM hydrogel capable of protecting healing tissues and reducing adhesion development in preclinical surgical models. These results support the potential of ECM hydrogel as a clinically translatable, biocompatible strategy for improving postsurgical healing outcomes and reducing adhesion-related complications.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241881","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}
Pub Date : 2025-10-08DOI: 10.1126/scitranslmed.adp9155
Ligia B. Schmitd, Hannah Hafner, Ayobami Ward, Elham Asghari Adib, Natalia P. Biscola, Rafi Kohen, Mitre Athaiya, Meghan Tuttle, Manav Patel, Rachel E. Williamson, Emily Desai, Julianna Bennett, Grace Saxman, David Wilborn, Jaisha Shumpert, Xiao-Feng Zhao, Riki Kawaguchi, Daniel H. Geschwind, Ahmet Hoke, Peter Shrager, Catherine A. Collins, Leif A. Havton, Ashley L. Kalinski, Roman J. Giger
Upon injury to the mammalian peripheral nervous system (PNS), severed axons undergo rapid SARM1-dependent programmed axon death (Wallerian degeneration), but a potential role for Sarm1 in PNS regeneration remains unclear. We show that in mouse dorsal root ganglia with their axons cut, Sarm1 delayed the activation of injury-induced transcriptional programs associated with axon outgrowth and immune function. After sciatic nerve crush in Sarm1−/− mice, axons rapidly extended through the nerve injury site, but growth stalled more distally. Slow axon regeneration in the distal nerve was accompanied by delayed induction of the nerve repair response by Schwann cells and delayed clearance of disintegrating myelin. Nerve fibers did regenerate in Sarm1−/− mice, but regeneration was delayed, and axons exhibited reduced caliber and aberrant target innervation. Tibial nerve action potentials were weaker, and recovery of hind paw function was delayed but ultimately not impaired. Grafting of mouse Sarm1−/− nerves into wild-type mice and mouse wild-type nerves into Sarm1−/− mice revealed that the Sarm1−/− nerve microenvironment was hostile to wild-type axon regeneration and, conversely, that Sarm1−/− axons robustly grew into mouse wild-type nerve grafts. Ex vivo, the appearance of c-Jun–labeled Schwann cells in cultured mouse Sarm1−/− nerves was delayed but could be accelerated by pharmacological inhibition of ErbB kinase. Our study highlights the opposing functions of Sarm1 deficiency in dorsal root ganglia and distal nerves in mice, the consequence of which is delayed PNS regeneration.
{"title":"Deletion of murine Sarm1 results in a microenvironment that delays peripheral nerve regeneration after injury","authors":"Ligia B. Schmitd, Hannah Hafner, Ayobami Ward, Elham Asghari Adib, Natalia P. Biscola, Rafi Kohen, Mitre Athaiya, Meghan Tuttle, Manav Patel, Rachel E. Williamson, Emily Desai, Julianna Bennett, Grace Saxman, David Wilborn, Jaisha Shumpert, Xiao-Feng Zhao, Riki Kawaguchi, Daniel H. Geschwind, Ahmet Hoke, Peter Shrager, Catherine A. Collins, Leif A. Havton, Ashley L. Kalinski, Roman J. Giger","doi":"10.1126/scitranslmed.adp9155","DOIUrl":"10.1126/scitranslmed.adp9155","url":null,"abstract":"<div >Upon injury to the mammalian peripheral nervous system (PNS), severed axons undergo rapid SARM1-dependent programmed axon death (Wallerian degeneration), but a potential role for <i>Sarm1</i> in PNS regeneration remains unclear. We show that in mouse dorsal root ganglia with their axons cut, <i>Sarm1</i> delayed the activation of injury-induced transcriptional programs associated with axon outgrowth and immune function. After sciatic nerve crush in <i>Sarm1<sup>−/−</sup></i> mice, axons rapidly extended through the nerve injury site, but growth stalled more distally. Slow axon regeneration in the distal nerve was accompanied by delayed induction of the nerve repair response by Schwann cells and delayed clearance of disintegrating myelin. Nerve fibers did regenerate in <i>Sarm1<sup>−/−</sup></i> mice, but regeneration was delayed, and axons exhibited reduced caliber and aberrant target innervation. Tibial nerve action potentials were weaker, and recovery of hind paw function was delayed but ultimately not impaired. Grafting of mouse <i>Sarm1<sup>−/−</sup></i> nerves into wild-type mice and mouse wild-type nerves into <i>Sarm1<sup>−/−</sup></i> mice revealed that the <i>Sarm1<sup>−/−</sup></i> nerve microenvironment was hostile to wild-type axon regeneration and, conversely, that <i>Sarm1<sup>−/−</sup></i> axons robustly grew into mouse wild-type nerve grafts. Ex vivo, the appearance of c-Jun–labeled Schwann cells in cultured mouse <i>Sarm1<sup>−/−</sup></i> nerves was delayed but could be accelerated by pharmacological inhibition of ErbB kinase. Our study highlights the opposing functions of <i>Sarm1</i> deficiency in dorsal root ganglia and distal nerves in mice, the consequence of which is delayed PNS regeneration.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241880","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}
Pub Date : 2025-10-08DOI: 10.1126/scitranslmed.adq3551
Ji Geng, Xiying Wang, Jie Pan, Danish Khan, Sopida Pimcharoen, Yongjie Zhang, Nima Mosammaparast, Susumu Hirose, Leonard Petrucelli, Onn Brandman, Lei S. Qi, Bingwei Lu
Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell–derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated ASCC3 variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the Fmr1 KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal Fmr1 KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive–like behavior, and social interaction deficits after 1 month in 2-month-old Fmr1 KO mice compared with untreated Fmr1 KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.
{"title":"CRISPR activation of the ribosome-associated quality control factor ASCC3 ameliorates fragile X syndrome phenotypes in mice","authors":"Ji Geng, Xiying Wang, Jie Pan, Danish Khan, Sopida Pimcharoen, Yongjie Zhang, Nima Mosammaparast, Susumu Hirose, Leonard Petrucelli, Onn Brandman, Lei S. Qi, Bingwei Lu","doi":"10.1126/scitranslmed.adq3551","DOIUrl":"10.1126/scitranslmed.adq3551","url":null,"abstract":"<div >Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell–derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated <i>ASCC3</i> variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the <i>Fmr1</i> KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal <i>Fmr1</i> KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive–like behavior, and social interaction deficits after 1 month in 2-month-old <i>Fmr1</i> KO mice compared with untreated <i>Fmr1</i> KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241878","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}
Pub Date : 2025-10-08DOI: 10.1126/scitranslmed.adw0358
Jonas Schmid, Chiara Alberti, Laura Power, Nicolás G. Nuñez, Donatella De Feo, Sofia Tyystjärvi, Laila Kulsvehagen, Victor Kreiner, Ana Beatriz Ayroza Bleher, Patrick Lipps, Stijn Swinnen, Florian Ingelfinger, Can Ulutekin, Camille Chaubet, Susanne Unger, Stefanie Kreutmair, Romain Marignier, Thomas Korn, Anne-Katrin Pröbstel, Roland Liblau, Burkhard Becher
Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is a recently defined neurological autoimmune condition. The pathogenesis of the disease remains poorly understood, and no specific therapies are currently approved. Here, a comprehensive single-cell immunophenotyping of peripheral blood mononuclear cells from two independent cohorts of patients with MOGAD revealed pronounced immune perturbations in MOGAD when compared with healthy controls and patients with multiple sclerosis. Patients with MOGAD displayed an expansion of CXCR5−CD21− activated naïve and double-negative B cell subsets, a feature shared with patients with systemic lupus erythematosus. In addition, we observed altered Fc gamma receptor expression in natural killer cells, monocytes, and dendritic cells. Within the T cell compartment, CXCR3+CD4+ memory T cells were reduced in the circulation of patients with MOGAD compared with healthy controls, and this result was mirrored in a transgenic mouse model that showed retention of these cells in the inflamed central nervous system. Together, these results demonstrate profound systemic immune cell alterations in MOGAD and contribute to a better understanding of this distinct disease entity.
{"title":"Immune signatures link myelin oligodendrocyte glycoprotein antibody–associated disease to other autoantibody-mediated conditions","authors":"Jonas Schmid, Chiara Alberti, Laura Power, Nicolás G. Nuñez, Donatella De Feo, Sofia Tyystjärvi, Laila Kulsvehagen, Victor Kreiner, Ana Beatriz Ayroza Bleher, Patrick Lipps, Stijn Swinnen, Florian Ingelfinger, Can Ulutekin, Camille Chaubet, Susanne Unger, Stefanie Kreutmair, Romain Marignier, Thomas Korn, Anne-Katrin Pröbstel, Roland Liblau, Burkhard Becher","doi":"10.1126/scitranslmed.adw0358","DOIUrl":"10.1126/scitranslmed.adw0358","url":null,"abstract":"<div >Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is a recently defined neurological autoimmune condition. The pathogenesis of the disease remains poorly understood, and no specific therapies are currently approved. Here, a comprehensive single-cell immunophenotyping of peripheral blood mononuclear cells from two independent cohorts of patients with MOGAD revealed pronounced immune perturbations in MOGAD when compared with healthy controls and patients with multiple sclerosis. Patients with MOGAD displayed an expansion of CXCR5<sup>−</sup>CD21<sup>−</sup> activated naïve and double-negative B cell subsets, a feature shared with patients with systemic lupus erythematosus. In addition, we observed altered Fc gamma receptor expression in natural killer cells, monocytes, and dendritic cells. Within the T cell compartment, CXCR3<sup>+</sup>CD4<sup>+</sup> memory T cells were reduced in the circulation of patients with MOGAD compared with healthy controls, and this result was mirrored in a transgenic mouse model that showed retention of these cells in the inflamed central nervous system. Together, these results demonstrate profound systemic immune cell alterations in MOGAD and contribute to a better understanding of this distinct disease entity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adw0358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241876","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}
Pub Date : 2025-10-08DOI: 10.1126/scitranslmed.adz1286
Pedro R. Lowenstein
Multiomics on serial glioblastoma biopsies can enable differentiation of pseudoprogression from true tumor progression (see Ling et al.).
连续胶质母细胞瘤活检的多组学可以区分假进展和真正的肿瘤进展（见Ling等人）。
{"title":"Now you see me; now you don’t","authors":"Pedro R. Lowenstein","doi":"10.1126/scitranslmed.adz1286","DOIUrl":"10.1126/scitranslmed.adz1286","url":null,"abstract":"<div >Multiomics on serial glioblastoma biopsies can enable differentiation of pseudoprogression from true tumor progression (see Ling <i>et al</i>.).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241879","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}
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