Yingying Qu, Wenhua Liang, Mingzhu Yu, Chenhui Wang, Min Luo, Lin Zhong, Zhigang Li, Feng Wang
{"title":"MYO1F in neutrophils is required for the response to immune checkpoint blockade therapy.","authors":"Yingying Qu, Wenhua Liang, Mingzhu Yu, Chenhui Wang, Min Luo, Lin Zhong, Zhigang Li, Feng Wang","doi":"10.1084/jem.20241957","DOIUrl":"https://doi.org/10.1084/jem.20241957","url":null,"abstract":"<p><p>Tumor-associated neutrophils (TANs) represent a significant barrier to the effectiveness of immune checkpoint blockade (ICB) therapy. A comprehensive understanding of TANs' regulatory mechanisms is therefore essential for predicting ICB efficacy and improving immunotherapy strategies. Our study reveals that MYO1F is selectively downregulated in neutrophils within both human cancers and murine tumor models, showing a negative correlation with ICB response. Mechanistically, MYO1F normally inhibits neutrophil immunosuppression and proliferation by restraining STAT3 activity. However, during tumorigenesis, tumor-derived TGF-β1 disrupts the binding of SPI1 to intron 8 of Myo1f via DNA methylation, thereby suppressing Myo1f transcription. The resultant decrease in MYO1F reprograms neutrophils into an immunosuppressive state through the STAT3-dependent signaling pathways. This immunosuppressive state further contributes to tumor microenvironment (TME) remodeling by inducing CTL exhaustion. These findings establish MYO1F as a critical regulator within TANs, highlighting its significant role in modulating ICB therapy efficacy.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 6","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810747","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}
Daniel Castranova, Madeleine I Kenton, Aurora Kraus, Christopher W Dell, Jong S Park, Marina Venero Galanternik, Gilseung Park, Daniel N Lumbantobing, Louis Dye, Miranda Marvel, James Iben, Kiyohito Taimatsu, Van Pham, Reegan J Willms, Lucas Blevens, Tanner F Robertson, Yiran Hou, Anna Huttenlocher, Edan Foley, Lynne R Parenti, J Kimble Frazer, Kedar Narayan, Brant M Weinstein
{"title":"The axillary lymphoid organ is an external, experimentally accessible immune organ in the zebrafish.","authors":"Daniel Castranova, Madeleine I Kenton, Aurora Kraus, Christopher W Dell, Jong S Park, Marina Venero Galanternik, Gilseung Park, Daniel N Lumbantobing, Louis Dye, Miranda Marvel, James Iben, Kiyohito Taimatsu, Van Pham, Reegan J Willms, Lucas Blevens, Tanner F Robertson, Yiran Hou, Anna Huttenlocher, Edan Foley, Lynne R Parenti, J Kimble Frazer, Kedar Narayan, Brant M Weinstein","doi":"10.1084/jem.20241435","DOIUrl":"10.1084/jem.20241435","url":null,"abstract":"<p><p>Lymph nodes and other secondary lymphoid organs play critical roles in immune surveillance and immune activation in mammals, but the deep internal locations of these organs make it challenging to image and study them in living animals. Here, we describe a previously uncharacterized external immune organ in the zebrafish ideally suited for studying immune cell dynamics in vivo, the axillary lymphoid organ (ALO). This small, translucent organ has an outer cortex teeming with immune cells, an inner medulla with a mesh-like network of fibroblastic reticular cells along which immune cells migrate, and a network of lymphatic vessels draining to a large adjacent lymph sac. Noninvasive high-resolution imaging of transgenically marked immune cells can be carried out in ALOs of living animals, which are readily accessible to external treatment. This newly discovered tissue provides a superb model for dynamic live imaging of immune cells and their interaction with pathogens and surrounding tissues, including blood and lymphatic vessels.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 6","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752887","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}
Devon Jeltema, Kennady Knox, Nicole Dobbs, Zhen Tang, Cong Xing, Antonina Araskiewicz, Kun Yang, Ivan Rodriguez Siordia, Jason Matthews, Michael Cohen, Nan Yan
{"title":"PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease.","authors":"Devon Jeltema, Kennady Knox, Nicole Dobbs, Zhen Tang, Cong Xing, Antonina Araskiewicz, Kun Yang, Ivan Rodriguez Siordia, Jason Matthews, Michael Cohen, Nan Yan","doi":"10.1084/jem.20241184","DOIUrl":"10.1084/jem.20241184","url":null,"abstract":"<p><p>Type I IFN (IFN-I) induce hundreds of antiviral genes as well as negative regulators that limit IFN-I signaling. Here, we investigate the family of 16 PARPs and find that 11 PARPs are ISGs, of which 8 PARPs inhibit IFN-I production. PARP7 is the most potent negative feedback regulator of IFN-I production. Using Parp7-/- and Parp7H532A/H532A mice, we show that PARP7 loss leads to systemic autoimmunity characterized by splenomegaly and increased autoantibodies and inflammatory cytokines. PARP7 loss also results in perivascular immune infiltration in the lung that forms tertiary lymphoid structures. Mechanistically, PARP7 inhibits multiple innate immune pathways in a cell-intrinsic and MARylation-dependent manner. PARP7 interacts with IRF3 through the catalytic domain and disrupts the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production. Irf3-/- or Irf3S1/S1 (transcription defective) or Sting-/- rescues Parp7H532A/H532A mouse autoimmunity and lung disease. Together, our study reveals physiological functions of PARP7 as a negative feedback regulator of IFN-I production that maintains immune homeostasis particularly in the lung.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449298","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}
Gnana P Krishnamoorthy, Anthony R Glover, Brian R Untch, Nickole Sigcha-Coello, Bin Xu, Dina Vukel, Yi Liu, Vera Tiedje, Jose Mario Bello Pineda, Katherine Berman, Prasanna P Tamarapu, Adrian Acuña-Ruiz, Mahesh Saqcena, Elisa de Stanchina, Laura Boucai, Ronald A Ghossein, Jeffrey A Knauf, Omar Abdel-Wahab, Robert K Bradley, James A Fagin
{"title":"RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs.","authors":"Gnana P Krishnamoorthy, Anthony R Glover, Brian R Untch, Nickole Sigcha-Coello, Bin Xu, Dina Vukel, Yi Liu, Vera Tiedje, Jose Mario Bello Pineda, Katherine Berman, Prasanna P Tamarapu, Adrian Acuña-Ruiz, Mahesh Saqcena, Elisa de Stanchina, Laura Boucai, Ronald A Ghossein, Jeffrey A Knauf, Omar Abdel-Wahab, Robert K Bradley, James A Fagin","doi":"10.1084/jem.20241029","DOIUrl":"10.1084/jem.20241029","url":null,"abstract":"<p><p>RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon inclusion events included vinculin (VCL), tenascin C (TNC), and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse HrasG12V/Rbm1OKO thyrocytes develop metastases that are reversed by RBM10 expression or by combined knockdown of VCL, CD44, and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusion in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFκB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483241","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":"Correction: Lymphatic transport in anti-tumor immunity and metastasis.","authors":"Mengzhu Sun, Julien Angelillo, Stéphanie Hugues","doi":"10.1084/jem.2023195403262025c","DOIUrl":"10.1084/jem.2023195403262025c","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784389","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}
Evi Duthoo, Elien Beyls, Lynn Backers, Thorkell Gudjónsson, Peiquan Huang, Leander Jonckheere, Sebastian Riemann, Bram Parton, Likun Du, Veronique Debacker, Marieke De Bruyne, Levi Hoste, Ans Baeyens, Anne Vral, Eva Van Braeckel, Jens Staal, Geert Mortier, Tessa Kerre, Qiang Pan-Hammarström, Claus S Sørensen, Filomeen Haerynck, Kathleen B M Claes, Simon J Tavernier
{"title":"Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients.","authors":"Evi Duthoo, Elien Beyls, Lynn Backers, Thorkell Gudjónsson, Peiquan Huang, Leander Jonckheere, Sebastian Riemann, Bram Parton, Likun Du, Veronique Debacker, Marieke De Bruyne, Levi Hoste, Ans Baeyens, Anne Vral, Eva Van Braeckel, Jens Staal, Geert Mortier, Tessa Kerre, Qiang Pan-Hammarström, Claus S Sørensen, Filomeen Haerynck, Kathleen B M Claes, Simon J Tavernier","doi":"10.1084/jem.20241432","DOIUrl":"10.1084/jem.20241432","url":null,"abstract":"<p><p>Ataxia telangiectasia and Rad3-related (ATR) kinase and its interacting protein ATRIP orchestrate the replication stress response. Homozygous splice variants in the ATRIP gene, resulting in ATRIP deficiency, were identified in two patients of independent ancestry with microcephaly, primordial dwarfism, and recurrent infections. The c.829+5G>T patient exhibited lymphopenia, poor vaccine responses, autoimmune features with hemolytic anemia, and neutropenia. Immunophenotyping revealed reduced CD16+/CD56dim NK cells and absent naïve T cells, MAIT cells, and iNKT cells. Lymphocytic defects were characterized by TCR oligoclonality, abnormal class switch recombination, and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation under genotoxic stress. ATRIP-deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-SelectTIME confirmed reduced cell fitness for both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP's critical role in protecting immune cells from replication stress, and offers new insights into its canonical functions.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542154","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":"PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion.","authors":"Wenxing Qin, Yuran Duan, Zhiqiang Hu, Yueru Hou, Ting Wen, Yuan Ouyang, Zheng Wang, Xue Sun, Xiaohan Chen, Katherine L Wang, Shudi Luo, Guimei Ji, Yuli Shen, Bofei Dong, Yanni Lin, Qi Tian, Zhanpeng Guo, Shiqi Wu, Ling Xiao, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Wuchang Zhang, Shengzhong Duan, Xueli Bai, Tong Liu, Jie He, Zhimin Lu, Daqian Xu","doi":"10.1084/jem.20240902","DOIUrl":"10.1084/jem.20240902","url":null,"abstract":"<p><p>Hypoxia induces immunosuppressive phenotypes in tumor cells even in the presence of cytosolic DNA accumulation. The mechanisms by which tumor cells suppress hypoxia-induced cGAS-STING activation for immune evasion remain largely unclear. Here, we demonstrate that hypoxic stimulation induces JNK1/2-mediated S151 phosphorylation of phosphoenolpyruvate carboxykinase 1 (PCK1), a rate-limiting enzyme in gluconeogenesis. This phosphorylation triggers the interaction between PCK1 and cGAS. The PCK1 associated with cGAS competitively consumes GTP, a substrate shared by both PCK1 and cGAS. Consequently, PCK1 inhibits GTP-dependent cGAS activation and subsequent STING-promoted immune cell infiltration and activation in the tumor microenvironment, leading to promoted tumor growth in mice. The blockade of PCK1 function, in combination with anti-PD-1 antibody treatment, exhibits an additive therapeutic effect on tumor growth. Additionally, PCK1 S151 phosphorylation is inversely correlated with cGAS-STING activation in human breast cancer specimens and patient survival. These findings reveal a novel regulation of cGAS-STING pathway and uncover the metabolic control of immune response in tumor cells.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566585","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":"An in-depth look at lung lymphatics.","authors":"David G Jackson","doi":"10.1084/jem.20250119","DOIUrl":"10.1084/jem.20250119","url":null,"abstract":"<p><p>In this issue of JEM, Cleary et al. (https://doi.org/10.1084/jem.20241359) present a new intravital imaging technique using a 3D-printed window device that enables lung lymphatics and their participation in immune cell trafficking events to be visualized in action for the first time in mechanically ventilated mice.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657475","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":"A \"second hit\" impacts disease severity in a dominantly inherited genetic skin disorder.","authors":"Pierre A Coulombe","doi":"10.1084/jem.20242377","DOIUrl":"10.1084/jem.20242377","url":null,"abstract":"<p><p>In this issue of JEM, Bergson et al. (https://doi.org/10.1084/jem.20240827) identified variants in HMCN1 that co-segregate with and account for variations in disease severity in individuals with a diagnosis of epidermolysis bullosa simplex (EBS) resulting from pathogenic variants in KRT14. The authors show that hemicentin-1 binds keratin 14 at the protein level and that silencing HMCN1 expression disrupts the organization of K14-containing filaments in epidermal keratinocytes and their attachment to the extracellular matrix. These findings address the clinical heterogeneity observed in EBS, a rare genetic skin disorder, with general implications for all genodermatoses.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457715","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}
Benjamin J Broomfield, Chin Wee Tan, Raymond Z Qin, Hanna Abberger, Brigette C Duckworth, Carolina Alvarado, Lennard Dalit, Chee Leng Lee, Rekha Shandre Mugan, Zihnil A I Mazrad, Hiromi Muramatsu, Liana Mackiewicz, Bailey E Williams, Jinjin Chen, Asuka Takanashi, Stewart Fabb, Marc Pellegrini, Kelly L Rogers, Woohyun J Moon, Colin W Pouton, Melissa J Davis, Stephen L Nutt, Norbert Pardi, Verena C Wimmer, Joanna R Groom
{"title":"Transient inhibition of type I interferon enhances CD8+ T cell stemness and vaccine protection.","authors":"Benjamin J Broomfield, Chin Wee Tan, Raymond Z Qin, Hanna Abberger, Brigette C Duckworth, Carolina Alvarado, Lennard Dalit, Chee Leng Lee, Rekha Shandre Mugan, Zihnil A I Mazrad, Hiromi Muramatsu, Liana Mackiewicz, Bailey E Williams, Jinjin Chen, Asuka Takanashi, Stewart Fabb, Marc Pellegrini, Kelly L Rogers, Woohyun J Moon, Colin W Pouton, Melissa J Davis, Stephen L Nutt, Norbert Pardi, Verena C Wimmer, Joanna R Groom","doi":"10.1084/jem.20241148","DOIUrl":"10.1084/jem.20241148","url":null,"abstract":"<p><p>Developing vaccines that promote CD8+ T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1+ stem cell-like memory CD8+ T (TSCM) cells are important determinants of long-lived memory. Yet, the developmental requirements for TSCM cell formation are unclear. Here, we identify the temporal window for type I interferon receptor (IFNAR) blockade to drive TSCM cell generation following viral infection and mRNA-lipid nanoparticle vaccination. We reveal a reversible developmental trajectory where transcriptionally distinct TSCM cells emerged from a transitional precursor of exhausted T cellular state concomitant with viral clearance. TSCM cell differentiation correlated with T cell retention within the lymph node paracortex due to disrupted CXCR3 chemokine gradient formation. These effects were linked to increased antigen load and a counterintuitive increase in IFNγ, which controlled cell location. Vaccination with the IFNAR blockade promoted TSCM cell differentiation and enhanced protection against chronic infection. These findings propose an approach to vaccine design whereby modulation of inflammation promotes memory formation and function.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585880","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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