Owen Leddy, Yuko Yuki, Mary Carrington, Bryan D Bryson, Forest M White
{"title":"Targeting infection-specific peptides in immunopeptidomics studies for vaccine target discovery.","authors":"Owen Leddy, Yuko Yuki, Mary Carrington, Bryan D Bryson, Forest M White","doi":"10.1084/jem.20250444","DOIUrl":"https://doi.org/10.1084/jem.20250444","url":null,"abstract":"<p><p>Vaccine-elicited T cell responses can contribute to immune protection against emerging infectious disease risks such as antimicrobial-resistant (AMR) microbial pathogens and viruses with pandemic potential, but rapidly identifying appropriate targets for T cell priming vaccines remains challenging. Mass spectrometry (MS) analysis of peptides presented on MHCs can identify potential targets for protective T cell responses in a proteome-wide manner. However, pathogen-derived peptides are outnumbered by self-peptides in the MHC repertoire and may be missed in untargeted MS analyses. Here, we present a novel approach, termed PathMHC, that uses computational analysis of untargeted MS data followed by targeted MS to discover novel pathogen-derived MHC peptides more efficiently than untargeted methods alone. We applied this workflow to identify MHC peptides derived from multiple microbes, including potential vaccine targets presented on MHC-I by human dendritic cells infected with Mycobacterium tuberculosis (Mtb), finding that all Mtb peptides detected in the MHC-I repertoire derived from proteins exported by type VII secretion systems. PathMHC will facilitate antigen discovery campaigns for vaccine development.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674939","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}
Usha Nair, Ziqi Feng, Madhav Akauliya, Abigail G Esposito, Charles R Crain, Edward D Lamperti, Thavaleak Prum, John E Warner, Lisa Madungwe, Gordon A Dale, Julie Boucau, Gaurav D Gaiha, Meng Yuan, Ian A Wilson, Facundo D Batista
{"title":"In vivo antibody diversification targeting a conserved coronavirus epitope.","authors":"Usha Nair, Ziqi Feng, Madhav Akauliya, Abigail G Esposito, Charles R Crain, Edward D Lamperti, Thavaleak Prum, John E Warner, Lisa Madungwe, Gordon A Dale, Julie Boucau, Gaurav D Gaiha, Meng Yuan, Ian A Wilson, Facundo D Batista","doi":"10.1084/jem.20241563","DOIUrl":"https://doi.org/10.1084/jem.20241563","url":null,"abstract":"<p><p>To explore the use of human B cell receptor (BCR) knock-in mice for broadening antibody responses, we diversified CR3022, a monoclonal antibody (mAb) originally identified in a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) convalescent patient. This mAb targets a conserved epitope on the coronavirus receptor-binding domain (RBD). We took advantage of high- and low-affinity CR3022 BCR knock-in mice and immunized them with SARS-CoV-2 Wuhan RBD trimers to expand the breadth of these antibodies toward this virus. The resulting antibodies retained the ability to neutralize SARS-CoV and exhibited enhanced affinity and neutralization against the SARS-CoV-2 WA1/2020 strain, as well as the Delta (B.1.617.2) and Omicron KP.3 variants. They also showed broadened reactivity to two bat coronaviruses: WIV1 and, to a lesser potency, BtKY72. Structural analysis revealed key mutations that enhanced binding and neutralization, highlighting the importance of epitope accessibility and variant-specific conformations in antibody diversification. These findings demonstrate that human BCR-expressing mouse models can generate effective antibodies with broad neutralizing activity against viral epitopes.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659311","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}
Kun Yang, Gustavo Torres-Ramirez, Nicole Dobbs, Jie Han, Makoto Asahina, Reiko Fujinawa, Kun Song, Yun Liu, Weichun Lin, Angelica Oviedo, Chuo Chen, Lei Zhu, William F Mueller, Kevin Lee, Tadashi Suzuki, Nan Yan
{"title":"The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency.","authors":"Kun Yang, Gustavo Torres-Ramirez, Nicole Dobbs, Jie Han, Makoto Asahina, Reiko Fujinawa, Kun Song, Yun Liu, Weichun Lin, Angelica Oviedo, Chuo Chen, Lei Zhu, William F Mueller, Kevin Lee, Tadashi Suzuki, Nan Yan","doi":"10.1084/jem.20242296","DOIUrl":"10.1084/jem.20242296","url":null,"abstract":"<p><p>The STING pathway is increasingly recognized as a key regulator of neuroinflammation in neurodegenerative disease, but its role in noninflammatory conditions remains unclear. We generated a postnatal inducible whole-body Ngly1 knockout mouse (iNgly1-/-) to model NGLY1 deficiency, an early-onset neurodegenerative disorder. iNgly1-/- mice exhibit progressive motor deficits, Purkinje cell loss, and shortened lifespan without evidence of gliosis or immune activation. Cell type-specific deletion of Ngly1 in Purkinje cells or microglia failed to induce disease, suggesting multiple cell-intrinsic and cell-extrinsic signals are required. Genetic ablation of Sting1 in iNgly1-/- mice rescues Purkinje cell loss, improves motor function, and extends lifespan. Single-nucleus RNA sequencing reveals proteostasis disruption in Purkinje cells, altered cerebellar granule cell subpopulations, and STING-dependent suppression of cholesterol biosynthesis in glia. Pharmacological inhibition of STING with an orally bioactive antagonist, VS-X4, significantly mitigates neuropathology and motor disease. These findings identify STING as a key mediator of neuropathology in NGLY1 deficiency and implicate a role of STING in noninflammatory neurological disease.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12249164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612174","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}
{"title":"Taking the STING out of neurodegenerative disease.","authors":"Aman Mangalmurti, John R Lukens","doi":"10.1084/jem.20250951","DOIUrl":"10.1084/jem.20250951","url":null,"abstract":"<p><p>New work from Yang et al. (https://doi.org/10.1084/jem.20242296) provides an exhaustive study of a novel mouse model of NGLY1 deficiency, a devastating neurological disease, and implicates the cGAS-STING pathway in mediating key disease features which can be rescued using an orally administered STING antagonist.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612173","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}
{"title":"Monoallelic mutations in MMD2 cause autosomal dominant aggressive periodontitis.","authors":"Tomoyuki Iwata, Yoko Mizoguchi, Tetsuya Yoshimoto, Miyuki Tsumura, Fumiaki Sakura, Jeffrey R Johnson, Shinji Matsuda, Kazuhisa Ouhara, Yukiko Nagatani, Takaki Asano, Hidenori Ohnishi, Zenichiro Kato, Keichiro Mihara, Hirokazu Kanegane, Tomoya Ueda, Shinya Sasaki, Yuri Taniguchi, Yurika Ninomiya, Yoshinori Ohno, Kyoko Suzuki-Takedachi, Yusuke Sotomaru, Tetsushi Sakuma, Takashi Yamamoto, Yukiko Matsuda, Kodai Kume, Terukazu Sanui, Fusanori Nishimura, Mikihito Kajiya, Yasuyoshi Ueki, Hidemi Kurihara, Hiroyuki Morino, Satoshi Okada, Hideshi Kawakami, Noriyoshi Mizuno","doi":"10.1084/jem.20231911","DOIUrl":"10.1084/jem.20231911","url":null,"abstract":"<p><p>Aggressive periodontitis causes rapid destruction of periodontal tissue. It occurs at a young age with familial clustering. We report on the first time on molecular and cellular basis of a Mendelian form of autosomal dominant aggressive periodontitis. Monoallelic mutations in the monocyte to macrophage differentiation-associated 2 (MMD2) gene, encoding MMD2, in two Japanese families with autosomal dominant aggressive periodontitis are identified. Mutations, c.347 C>T (p.A116V) and c.377 G>C (p.R126P) in MMD2, disturbed fMLP-induced activation of Ras/ERK signaling. Additionally, abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients' neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 mutation. Our studies revealed that monoallelic mutations in MMD2 underlie the impairment of neutrophil chemotaxis, which leads to the development of autosomal dominant aggressive periodontitis.</p>","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/PMC12262042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637124","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}
Heather J Faust, Margaret H Chang, A Helena Jonsson, Erin Theisen, Nelson M LaMarche, William V Trim, Lydia Lynch, Peter A Nigrovic, Michael B Brenner
{"title":"Adipose tissue harbors pathogenic T cells in obesity that exacerbate inflammatory arthritis.","authors":"Heather J Faust, Margaret H Chang, A Helena Jonsson, Erin Theisen, Nelson M LaMarche, William V Trim, Lydia Lynch, Peter A Nigrovic, Michael B Brenner","doi":"10.1084/jem.20240677","DOIUrl":"10.1084/jem.20240677","url":null,"abstract":"<p><p>Obesity worsens inflammatory arthritis severity, even in non-load-bearing joints, but the mechanism is unknown. Here, we show that there is an immunological mechanism mediated by T cells in adipose tissue. Using an antigen-induced arthritis model with trackable, arthritis-inducing CD8+ OT-I T cells, we found that OT-I T cells home to visceral adipose tissue (VAT) and expand there in the obese high-fat diet (HFD) context. Transplant of VAT from arthritic mice increased arthritis severity in naïve recipient mice and was ameliorated by CD8 T cell depletion. Bulk RNA sequencing identified pro-inflammatory changes to OT-I T cells in VAT characterized by increased IFN α and γ signaling after HFD. Intraperitoneal injection of IFNα, but not IFNγ, expanded CD8 T cell numbers in VAT. HFD-induced expansion of VAT CD8 T cells was ameliorated with global Ifnar1 deletion, and importantly, genetic deletion of Ifnar1 in T cells decreased arthritis severity in obese mice. These results provide a mechanistic explanation of how obesity worsens autoimmunity.</p>","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/PMC12263171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575616","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}
Sangya Chatterjee, Tamina Rückert, Ina Martin, Elisa Michaeli, Joerg Buescher, Petya Apostolova, Daniel Erny, Maria-Eleni Lalioti, Francesca Biavasco, Alina Hartmann, Solveig Runge, Lukas M Braun, Nana Talvard-Balland, Rachael C Adams, Annette Schmitt-Graeff, James Cook, Valentin Wenger, Dimitrios Athanassopoulos, Dilara Hasavci, Alexander Paolo Vallejo-Janeta, Thomas Blank, Philipp Schaible, Janaki Manoja Vinnakota, Alexander Zähringer, Stephanie C Ganal-Vonarburg, Wolfgang Melchinger, Dietmar Pfeifer, Natalie Köhler, Stephan P Rosshart, David Michonneau, Gérard Socié, Geoffroy Andrieux, Nina Cabezas-Wallscheid, Melanie Boerries, Marco Prinz, Robert Zeiser
{"title":"Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD.","authors":"Sangya Chatterjee, Tamina Rückert, Ina Martin, Elisa Michaeli, Joerg Buescher, Petya Apostolova, Daniel Erny, Maria-Eleni Lalioti, Francesca Biavasco, Alina Hartmann, Solveig Runge, Lukas M Braun, Nana Talvard-Balland, Rachael C Adams, Annette Schmitt-Graeff, James Cook, Valentin Wenger, Dimitrios Athanassopoulos, Dilara Hasavci, Alexander Paolo Vallejo-Janeta, Thomas Blank, Philipp Schaible, Janaki Manoja Vinnakota, Alexander Zähringer, Stephanie C Ganal-Vonarburg, Wolfgang Melchinger, Dietmar Pfeifer, Natalie Köhler, Stephan P Rosshart, David Michonneau, Gérard Socié, Geoffroy Andrieux, Nina Cabezas-Wallscheid, Melanie Boerries, Marco Prinz, Robert Zeiser","doi":"10.1084/jem.20242180","DOIUrl":"https://doi.org/10.1084/jem.20242180","url":null,"abstract":"<p><p>Acute graft-versus-host disease (aGVHD) can affect the central nervous system (CNS) through microglial activation and T cell infiltration, but the role of gut microbiota in CNS-aGVHD remains unclear. Here, we investigated the role of microbiota in microglial activation during aGVHD using antibiotic-treated specific pathogen-free (SPF), germ-free (GF), and wildling mice. Antibiotic-mediated microbiota depletion led to infiltration of IFN-γ-producing T cells in the brain, activation of microglia via the TLR4/p38 MAPK pathway, and neurocognitive deficits in SPF aGVHD mice. Microglial depletion reversed the neurocognitive deficits. GF and wildling mice treated with antibiotics exhibited similar microglial activation after allogeneic hematopoietic cell transplantation (allo-HCT). Mechanistically, the bacteria-derived metabolite N,N,N-trimethyl-5-aminovaleric acid (TMAVA) was decreased in microglia following antibiotic treatment. TMAVA administration suppressed TLR4/p38 MAPK pathway activity in microglia and alleviated gut microbiota depletion-mediated neurocognitive deficits. Additionally, TMAVA abundance decreased in patient blood after allo-HCT and after GVHD onset. In summary, we identify TMAVA loss as a central causative factor for CNS-aGVHD, opening new perspectives for a metabolite-based therapy.</p>","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":"144584081","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}
Jorden I Lane, Elida Nieves-Ortiz, Ornella Ndatabaye, Aliia R Fatkhullina, Sebastian Lopez, Terence S Dermody, Daria Esterházy
{"title":"Intestinal lymphatic vasculature is functionally adapted to different drainage regions and is altered by helminth infection.","authors":"Jorden I Lane, Elida Nieves-Ortiz, Ornella Ndatabaye, Aliia R Fatkhullina, Sebastian Lopez, Terence S Dermody, Daria Esterházy","doi":"10.1084/jem.20241181","DOIUrl":"10.1084/jem.20241181","url":null,"abstract":"<p><p>We sought to determine whether the lymphatic vasculature functionally adapts to the organ in which it resides, such as along the gut. Duodenal lymphatic capillaries (lacteals) displayed the most discontinuous tight junction composition within the gut, resulting in a dependence on duodenal lacteals for rapid dietary lipid uptake. Duodenal helminths abrogated these features. Parallel RNA sequencing of lymphatic endothelial cells and mucosa along the intestine revealed that the transcriptomes overlapped in functional profiles. RNA sequencing also identified a putative VEGFR-2/3 signaling gradient that may explain differences in lacteal tight junctions along the small intestine at homeostasis. Transcriptionally, helminth infection triggered antimicrobial and angiogenic responses. While microbial depletion acted additively to helminths on lymphatic restructuring, glucocorticoids partially reversed helminth-induced lacteal changes. This suggests helminths induce lymphangiogenesis and associated lymphatic \"zippering\" via inflammation. Our study uncovers and explains the superior lipid absorption by duodenal lacteals and how it is compromised by helminths and provides transcriptional insights into lymphatic function along the gut.</p>","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/PMC12162095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144284907","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}
Quin T Waterbury, Jin Qian, Hualong Zheng, Amanda Dirnberger, Oakley C Olson, Ruth A White, Feijing Wu, Hiroki Kobayashi, Ermanno Malagola, Yosuke Ochiai, Ruhong Tu, Biyun Zheng, Adama Diaby, Harry Nagendra, Jonathan S LaBella, Leah Zamechek, Judith Korner, Ana B Emiliano, Anthony W Ferrante, Emmanuelle Passegué, Timothy C Wang
{"title":"Bone marrow neutrophil density regulates myelopoiesis during obesity and weight loss.","authors":"Quin T Waterbury, Jin Qian, Hualong Zheng, Amanda Dirnberger, Oakley C Olson, Ruth A White, Feijing Wu, Hiroki Kobayashi, Ermanno Malagola, Yosuke Ochiai, Ruhong Tu, Biyun Zheng, Adama Diaby, Harry Nagendra, Jonathan S LaBella, Leah Zamechek, Judith Korner, Ana B Emiliano, Anthony W Ferrante, Emmanuelle Passegué, Timothy C Wang","doi":"10.1084/jem.20242174","DOIUrl":"10.1084/jem.20242174","url":null,"abstract":"<p><p>The bone marrow (BM) is altered in obesity to promote myeloid cell generation, but the mechanisms driving these changes remain unclear. Here, we show that obesogenic stimuli promote adipose tissue macrophages to recruit neutrophils from the BM in mice. Recruitment of BM neutrophils activates hematopoietic stem cells, which produce myeloid cells that accumulate in the circulation and drive inflammation. This recruitment is not resolved by weight loss, leading to sustained myelopoiesis in previously obese mice. Inhibiting neutrophil recruitment out of the BM in obese mice or during weight loss reduces BM myelopoiesis and adipose tissue inflammation, and improves glucose tolerance. In humans with obesity, plasma neutrophil chemokines are increased, correlate with increased insulin resistance, but do not decrease with weight loss. Our results demonstrate that neutrophil recruitment is a key mediator of myelopoiesis during obesity, and targeting this pathway is a potential strategy to improve inflammation during obesity and weight loss.</p>","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/PMC12263173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612172","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}
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":"<p><p>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.</p>","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}
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