Journal of Experimental Medicine最新文献_第6页

Myeloid-targeting immunotherapies overcome inhibitory barriers in immune-evasive neuroblastoma. 骨髓靶向免疫疗法克服免疫逃避性神经母细胞瘤的抑制屏障。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-07-14 DOI: 10.1084/jem.20231417

Marie Ménard, Hiroyuki Yoda, Nicole Nasholm, Megumi J Barata, Linyu Wang, Erin F Simonds, Edbert D Lu, Shannon Wong-Michalak, Lauren McHenry, Alvin Farrel, Rebecca Kaufman, Vanessa Lopez, Rebekah J Kennedy, G Esteban Fernandez, Hiroyuki Shimada, Liron D Grossmann, Shahab Asgharzadeh, John M Maris, W Clay Gustafson, William A Weiss

{"title":"Myeloid-targeting immunotherapies overcome inhibitory barriers in immune-evasive neuroblastoma.","authors":"Marie Ménard, Hiroyuki Yoda, Nicole Nasholm, Megumi J Barata, Linyu Wang, Erin F Simonds, Edbert D Lu, Shannon Wong-Michalak, Lauren McHenry, Alvin Farrel, Rebecca Kaufman, Vanessa Lopez, Rebekah J Kennedy, G Esteban Fernandez, Hiroyuki Shimada, Liron D Grossmann, Shahab Asgharzadeh, John M Maris, W Clay Gustafson, William A Weiss","doi":"10.1084/jem.20231417","DOIUrl":"10.1084/jem.20231417","url":null,"abstract":"Neuroblastomas are highly heterogeneous tumors originating from neural crest-derived cells destined to form the sympathetic nervous system. Nearly half of high-risk tumors present with amplification of the MYCN proto-oncogene. Here, we describe a Mycn-driven, transplantable, non-germline, genetically engineered mouse model (Mycn-nGEMM). Mycn-nGEMM tumors recapitulate the immune-evasive, macrophage-rich tumor microenvironment of high-risk, MYCN-amplified human neuroblastoma. Treatment of tumor-bearing mice with anti-PD-L1, but not anti-PD-1 or anti-CTLA-4, inhibited tumor growth, profoundly remodeling the tumor microenvironment by depleting anti-inflammatory macrophages and increasing T cell infiltration. Surprisingly, while tumor cells showed low expression of PD-L1, anti-inflammatory macrophages from both murine and human neuroblastoma expressed PD-L1. We identified cytokines, including macrophage migration inhibitory factor, secreted by the Mycn-nGEMM cancer cells that drive expression of PD-L1 on macrophages. Combining anti-PD-L1 with CD40 agonist antibodies further improved survival in Mycn-nGEMM mice, demonstrating the potential for myeloid-targeting immunotherapies to overcome inhibitory barriers in immune-evasive neuroblastoma.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626474","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

Membrane-IL12 adjuvant mRNA vaccine polarizes pre-effector T cells for optimized tumor control. 膜- il - 12佐剂mRNA疫苗极化前效应T细胞，优化肿瘤控制。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-06-06 DOI: 10.1084/jem.20241454

Kun Peng, Xiaoxue Zhao, Hongjian Li, Yang-Xin Fu, Yong Liang

{"title":"Membrane-IL12 adjuvant mRNA vaccine polarizes pre-effector T cells for optimized tumor control.","authors":"Kun Peng, Xiaoxue Zhao, Hongjian Li, Yang-Xin Fu, Yong Liang","doi":"10.1084/jem.20241454","DOIUrl":"10.1084/jem.20241454","url":null,"abstract":"Conventional mRNA cancer vaccines can expand the quantity of tumor-specific CD8 T cells, but their effector function might be compromised. Specific cytokine signaling may enhance T cell differentiation for better tumor killing. We screened various cytokines and identified IL-12 as a potent adjuvant for mRNA vaccines, though with significant systemic toxicity. To balance efficacy and toxicity, we developed a membrane-tethered IL-12 (mtIL12) adjuvant mRNA vaccine. This design restricts mtIL12 expression to the surface of antigen-presenting cells, thereby selectively activating antigen-specific T cells without affecting bystander T or NK cells. mtIL12 adjuvant mRNA vaccination induced a unique pre-effector T cell subset that gives rise to highly responsive effector T cells, resulting in superior anti-tumor activity. Moreover, this approach overcame immune checkpoint therapy resistance and prevented cancer metastasis. Our study highlights that next-generation mRNA vaccines encoding membrane-tethered cytokine adjuvants can generate potent effector T cells, offering effective tumor control with reduced toxicity.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248195","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

Filamin A editing in myeloid cells reduces intestinal inflammation and protects from colitis. 在髓细胞中编辑丝蛋白A可以减少肠道炎症并防止结肠炎。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-06-05 DOI: 10.1084/jem.20240109

Riem Gawish, Rajagopal Varada, Florian Deckert, Anastasiya Hladik, Linda Steinbichl, Laura Cimatti, Katarina Milanovic, Mamta Jain, Natalya Torgasheva, Andrea Tanzer, Kim De Paepe, Tom Van de Wiele, Bela Hausmann, Michaela Lang, Martin Pechhacker, Nahla Ibrahim, Ingrid De Vries, Christine Brostjan, Michael Sixt, Christoph Gasche, Louis Boon, David Berry, Michael F Jantsch, Fatima C Pereira, Cornelia Vesely

{"title":"Filamin A editing in myeloid cells reduces intestinal inflammation and protects from colitis.","authors":"Riem Gawish, Rajagopal Varada, Florian Deckert, Anastasiya Hladik, Linda Steinbichl, Laura Cimatti, Katarina Milanovic, Mamta Jain, Natalya Torgasheva, Andrea Tanzer, Kim De Paepe, Tom Van de Wiele, Bela Hausmann, Michaela Lang, Martin Pechhacker, Nahla Ibrahim, Ingrid De Vries, Christine Brostjan, Michael Sixt, Christoph Gasche, Louis Boon, David Berry, Michael F Jantsch, Fatima C Pereira, Cornelia Vesely","doi":"10.1084/jem.20240109","DOIUrl":"10.1084/jem.20240109","url":null,"abstract":"Patho-mechanistic origins of ulcerative colitis are still poorly understood. The actin cross-linker filamin A (FLNA) impacts cellular responses through interaction with cytosolic proteins. Posttranscriptional A-to-I editing generates two forms of FLNA: genome-encoded FLNAQ and FLNAR. FLNA is edited in colon fibroblasts, smooth muscle cells, and endothelial cells. We found that the FLNA editing status determines colitis severity. Editing was highest in healthy colons and reduced during murine and human colitis. Mice that exclusively express FLNAR were highly resistant to DSS-induced colitis, whereas fully FLNAQ animals developed severe inflammation. While the genetic induction of FLNA editing influenced transcriptional states of structural cells and microbiome composition, we found that FLNAR exerts protection specifically via myeloid cells, which are physiologically unedited. Introducing fixed FLNAR did not hamper cell migration but reduced macrophage inflammation and rendered neutrophils less prone to NETosis. Thus, loss of FLNA editing correlates with colitis severity, and targeted editing of myeloid cells serves as a novel therapeutic approach in intestinal inflammation.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225670","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

S1PR1, an endothelial-immune influencer. S1PR1，内皮免疫影响因子。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-07-15 DOI: 10.1084/jem.20251056

Samantha Mahfoud, Timothy P Padera

引用次数: 0

Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages. 肿瘤指示的谷氨酰胺合成在癌症相关成纤维细胞中促进肿瘤前巨噬细胞。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-07-16 DOI: 10.1084/jem.20241426

Xiaoyun Li, Sofie Hedlund Møller, Jaeoh Park, Yu-Ming Chuang, Pei-Chun Hsueh, Tzu-Hsuan Chang, Kung-Chi Kao, Hector Gallart-Ayala, Yi-Hao Wang, Jhan-Jie Peng, Alessio Bevilacqua, Yi-Ru Yu, Zhiyu Li, Yann Kieffer, Domitille Peigney, Hugo Croizer, Yingxi Xu, Alfred Zippelius, Isabel C Lopez-Mejia, Lluis Fajas, Fatima Mechta-Grigoriou, Julijana Ivanisevic, Zhengtao Xiao, Ming-Chih Ho, Ying-Chun Shen, Ping-Chih Ho

{"title":"Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.","authors":"Xiaoyun Li, Sofie Hedlund Møller, Jaeoh Park, Yu-Ming Chuang, Pei-Chun Hsueh, Tzu-Hsuan Chang, Kung-Chi Kao, Hector Gallart-Ayala, Yi-Hao Wang, Jhan-Jie Peng, Alessio Bevilacqua, Yi-Ru Yu, Zhiyu Li, Yann Kieffer, Domitille Peigney, Hugo Croizer, Yingxi Xu, Alfred Zippelius, Isabel C Lopez-Mejia, Lluis Fajas, Fatima Mechta-Grigoriou, Julijana Ivanisevic, Zhengtao Xiao, Ming-Chih Ho, Ying-Chun Shen, Ping-Chih Ho","doi":"10.1084/jem.20241426","DOIUrl":"https://doi.org/10.1084/jem.20241426","url":null,"abstract":"In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared with normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs) and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME. Mechanistically, we found that tumor-derived palmitic acid activates a signaling cascade involving TLR4, Syk, and NF-κB in fibroblasts, leading to inflammatory CAF polarization and IL-6-induced glutamine synthesis. These findings uncover a novel metabolic symbiosis whereby tumor cells manipulate TAM polarization through CAF-mediated glutamine metabolism, presenting potential therapeutic targets for cancer immunotherapy.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642739","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

Epigenetic priming as a driver of memory recall and dysfunction in T cells. 表观遗传启动作为T细胞记忆回忆和功能障碍的驱动因素。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-07-31 DOI: 10.1084/jem.20241433

Mieke Metzemaekers, Niels J Rinzema, Ralph Stadhouders

引用次数: 0

Epitope and HLA specificity of human TCRs against Plasmodium falciparum circumsporozoite protein. 人抗恶性疟原虫环孢子子蛋白TCRs的表位和HLA特异性。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-07-10 DOI: 10.1084/jem.20250044

Hannah van Dijk, Ilka Wahl, Sara Kraker, Paul M Robben, Sheetij Dutta, Hedda Wardemann

{"title":"Epitope and HLA specificity of human TCRs against Plasmodium falciparum circumsporozoite protein.","authors":"Hannah van Dijk, Ilka Wahl, Sara Kraker, Paul M Robben, Sheetij Dutta, Hedda Wardemann","doi":"10.1084/jem.20250044","DOIUrl":"10.1084/jem.20250044","url":null,"abstract":"Plasmodium falciparum malaria remains a significant global health challenge. Current vaccines elicit antibody responses against circumsporozoite protein (PfCSP) that prevent the infection of hepatocytes but offer only moderate protection. Cellular immunity has emerged as a critical component of preerythrocytic protection that might be leveraged to develop improved PfCSP vaccines. Here, we characterized the clonality, molecular features, epitope specificity, and HLA restrictions of the human PfCSP-specific CD4+ and CD8+ T cell response to vaccination with an adjuvanted PfCSP vaccine, FMP013/ALFQ. Using TCR expression cloning, we identified novel conserved CD4+ T cell epitopes in the PfCSP N terminus and showed that the C-terminal CS.T3 epitope was targeted by CD4+ and rare CD8+ T cells, which recognized this epitope co-receptor independently presented on a class II HLA. Our findings provide insights into the utility of these epitopes as targets for strain-transcending immunity compared with the immunodominant but highly polymorphic epitopes in the PfCSP C terminus, offering guidance for the design of improved malaria vaccines.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600621","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

Antibiotics unleash neuroinflammation. 抗生素会引发神经炎症。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-08-19 DOI: 10.1084/jem.20251233

Jessica E Kenison, Francisco J Quintana

引用次数: 0

Correction: Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord. 校正：损伤小鼠脊髓细胞异质性和相互作用的单细胞分析。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-08-11 DOI: 10.1084/jem.2021004007232025c

Lindsay M Milich, James S Choi, Christine Ryan, Susana R Cerqueira, Sofia Benavides, Stephanie L Yahn, Pantelis Tsoulfas, Jae K Lee

引用次数: 0

Heart of the matter: Neutrophils, cancer, and cardiovascular disease. 问题的核心：中性粒细胞、癌症和心血管疾病。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-08-11 DOI: 10.1084/jem.20242402

Saira Ambreen, Afshan McCarthy, Andrés Hidalgo, Jose M Adrover

{"title":"Heart of the matter: Neutrophils, cancer, and cardiovascular disease.","authors":"Saira Ambreen, Afshan McCarthy, Andrés Hidalgo, Jose M Adrover","doi":"10.1084/jem.20242402","DOIUrl":"https://doi.org/10.1084/jem.20242402","url":null,"abstract":"Cancer and cardiovascular disease together are leading causes of death worldwide, and cancer patients display an abnormally elevated burden of cardiovascular disease. Neutrophils-key immune cells known primarily by their roles in inflammation and infection-can link these two pathological conditions. Neutrophils contribute to cancer progression and cardiovascular complications through various mechanisms, including their ability to promote inflammation, thrombosis, and vascular damage by interacting with vascular endothelial cells, platelets, and other immune cells, or by forming NETs. In cancer, neutrophils contribute to a hypercoagulability state, which promotes tumor growth and metastasis, and can also lead to thrombotic events, myocardial infarction, and stroke. Cancer affects neutrophil numbers and functional properties, induces the appearance of several neutrophil subtypes, and can alter hematopoiesis. Here we summarize the links between cancer and cardiovascular disease, focusing on the role of neutrophils and cancer-elicited changes to their function in connecting these two disease states and highlighting the neutrophils' dynamic interaction with both diseases.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816851","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