Journal of Experimental Medicine最新文献_第8页

JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL. JNK1 抑制剂可靶向远端 B 细胞受体信号转导，克服 CLL 中 BTK 抑制剂的耐药性。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-21 DOI: 10.1084/jem.20230681

Shifa Khaja Saleem, Sarah Decker, Sandra Kissel, Marcus Bauer, Dmitry Chernyakov, Daniela Bräuer-Hartmann, Konrad Aumann, Claudia Wickenhauser, Marco Herling, Oleksandra Skorobohatko, Nimitha Mathew, Cornelius Schmidt, Claudius Klein, Marie Follo, Christine Dierks

{"title":"JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL.","authors":"Shifa Khaja Saleem, Sarah Decker, Sandra Kissel, Marcus Bauer, Dmitry Chernyakov, Daniela Bräuer-Hartmann, Konrad Aumann, Claudia Wickenhauser, Marco Herling, Oleksandra Skorobohatko, Nimitha Mathew, Cornelius Schmidt, Claudius Klein, Marie Follo, Christine Dierks","doi":"10.1084/jem.20230681","DOIUrl":"10.1084/jem.20230681","url":null,"abstract":"Inhibition of the proximal B cell receptor (BCR) signaling pathway by BTK inhibitors is highly effective in the treatment of CLL, but drug resistance or intolerance occurs. Here, we investigated c-Jun N-terminal protein kinase 1 (JNK1) as an alternative drug target in the distal BCR pathway. JNK1 was preferentially overexpressed and activated in poor prognostic CLL with unmutated IGHV. Proximal BCR inhibition (BTK, PI3K, or SYK inhibitors) or SYK knockdown efficiently dephosphorylated JNK1, identifying JNK1 as a critical BCR downstream kinase in CLL. JNK1 inhibition induced apoptosis in primary CLL cells, resulting in the downregulation of BCL2, MCL1, and c-JUN. JNK1 inhibition in patient-derived CLL xenografted mice and Eµ-TCL1-tg mice prevented CLL progression, reduced splenic infiltration, and restored T cell function and normal hematopoiesis. JNK1 inhibitors even remained effective in ibrutinib refractory CLL. In conclusion, our study revealed JNK1 as a promising drug target in CLL downstream of the BCR, overcoming ibrutinib resistance, blocking the protective microenvironment, and improving CLL-specific immunosuppressive mechanisms.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681723","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

Human DBR1 deficiency impairs stress granule-dependent PKR antiviral immunity. 人类DBR1缺乏损害应激颗粒依赖性PKR抗病毒免疫。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-05 DOI: 10.1084/jem.20240010

Shuo Ru, Sisi Tang, Hui Xu, Jiahao Yin, Yan Guo, Liuping Song, Zhenyu Jin, Danyel Lee, Yi-Hao Chan, Xingyao Chen, Luke Buerer, William Fairbrother, Weidong Jia, Jean-Laurent Casanova, Shen-Ying Zhang, Daxing Gao

{"title":"Human DBR1 deficiency impairs stress granule-dependent PKR antiviral immunity.","authors":"Shuo Ru, Sisi Tang, Hui Xu, Jiahao Yin, Yan Guo, Liuping Song, Zhenyu Jin, Danyel Lee, Yi-Hao Chan, Xingyao Chen, Luke Buerer, William Fairbrother, Weidong Jia, Jean-Laurent Casanova, Shen-Ying Zhang, Daxing Gao","doi":"10.1084/jem.20240010","DOIUrl":"10.1084/jem.20240010","url":null,"abstract":"The molecular mechanism by which inborn errors of the human RNA lariat-debranching enzyme 1 (DBR1) underlie brainstem viral encephalitis is unknown. We show here that the accumulation of RNA lariats in human DBR1-deficient cells interferes with stress granule (SG) assembly, promoting the proteasome degradation of at least G3BP1 and G3BP2, two key components of SGs. In turn, impaired assembly of SGs, which normally recruit PKR, impairs PKR activation and activity against viruses, including HSV-1. Remarkably, the genetic ablation of PKR abolishes the corresponding antiviral effect of DBR1 in vitro. We also show that Dbr1Y17H/Y17H mice are susceptible to similar viral infections in vivo. Moreover, cells and brain samples from Dbr1Y17H/Y17H mice exhibit decreased G3BP1/2 expression and PKR phosphorylation. Thus, the debranching of RNA lariats by DBR1 permits G3BP1/2- and SG assembly-mediated PKR activation and cell-intrinsic antiviral immunity in mice and humans. DBR1-deficient patients are prone to viral disease because of intracellular lariat accumulation, which impairs G3BP1/2- and SG assembly-dependent PKR activation.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785911","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

Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency. ITPR3 的显性负变异会损害 T 细胞 Ca2+ 动力，导致联合免疫缺陷症。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-19 DOI: 10.1084/jem.20220979

Elena Blanco, Carme Camps, Sameer Bahal, Mohit D Kerai, Matteo P Ferla, Adam M Rochussen, Adam E Handel, Zainab M Golwala, Helena Spiridou Goncalves, Susanne Kricke, Fabian Klein, Fang Zhang, Federica Zinghirino, Grace Evans, Thomas M Keane, Sabrina Lizot, Maaike A A Kusters, Mildred A Iro, Sanjay V Patel, Emma C Morris, Siobhan O Burns, Ruth Radcliffe, Pradeep Vasudevan, Arthur Price, Olivia Gillham, Gabriel E Valdebenito, Grant S Stewart, Austen Worth, Stuart P Adams, Michael Duchen, Isabelle André, David J Adams, Giorgia Santili, Kimberly C Gilmour, Georg A Holländer, E Graham Davies, Jenny C Taylor, Gillian M Griffiths, Adrian J Thrasher, Fatima Dhalla, Alexandra Y Kreins

{"title":"Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.","authors":"Elena Blanco, Carme Camps, Sameer Bahal, Mohit D Kerai, Matteo P Ferla, Adam M Rochussen, Adam E Handel, Zainab M Golwala, Helena Spiridou Goncalves, Susanne Kricke, Fabian Klein, Fang Zhang, Federica Zinghirino, Grace Evans, Thomas M Keane, Sabrina Lizot, Maaike A A Kusters, Mildred A Iro, Sanjay V Patel, Emma C Morris, Siobhan O Burns, Ruth Radcliffe, Pradeep Vasudevan, Arthur Price, Olivia Gillham, Gabriel E Valdebenito, Grant S Stewart, Austen Worth, Stuart P Adams, Michael Duchen, Isabelle André, David J Adams, Giorgia Santili, Kimberly C Gilmour, Georg A Holländer, E Graham Davies, Jenny C Taylor, Gillian M Griffiths, Adrian J Thrasher, Fatima Dhalla, Alexandra Y Kreins","doi":"10.1084/jem.20220979","DOIUrl":"10.1084/jem.20220979","url":null,"abstract":"The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668028","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

Genetic and environmental risks for clonal hematopoiesis and cancer. 克隆造血和癌症的遗传和环境风险。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-03 DOI: 10.1084/jem.20230931

Stephanie Franco, Lucy A Godley

引用次数: 0

Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis. 免疫治疗相关结肠炎患者肠道菌群的基线结肠炎原性和急性紊乱。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-12 DOI: 10.1084/jem.20232079

Joan Shang, Diane Marie Del Valle, Graham J Britton, K R Mead, Urvija Rajpal, Alice Chen-Liaw, Ilaria Mogno, Zhihua Li, Rajita Menon, Edgar Gonzalez-Kozlova, Arielle Elkrief, Jonathan U Peled, Tina Ruth Gonsalves, Neil J Shah, Michael Postow, Jean-Frederic Colombel, Sacha Gnjatic, David M Faleck, Jeremiah J Faith

{"title":"Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis.","authors":"Joan Shang, Diane Marie Del Valle, Graham J Britton, K R Mead, Urvija Rajpal, Alice Chen-Liaw, Ilaria Mogno, Zhihua Li, Rajita Menon, Edgar Gonzalez-Kozlova, Arielle Elkrief, Jonathan U Peled, Tina Ruth Gonsalves, Neil J Shah, Michael Postow, Jean-Frederic Colombel, Sacha Gnjatic, David M Faleck, Jeremiah J Faith","doi":"10.1084/jem.20232079","DOIUrl":"10.1084/jem.20232079","url":null,"abstract":"Immunotherapy-related colitis (irC) frequently emerges as an immune-related adverse event during immune checkpoint inhibitor therapy and is presumably influenced by the gut microbiota. We longitudinally studied microbiomes from 38 ICI-treated cancer patients. We compared 13 ICI-treated subjects who developed irC against 25 ICI-treated subjects who remained irC-free, along with a validation cohort. Leveraging a preclinical mouse model, predisease stools from irC subjects induced greater colitigenicity upon transfer to mice. The microbiota during the first 10 days of irC closely resembled inflammatory bowel disease microbiomes, with reduced diversity, increased Proteobacteria and Veillonella, and decreased Faecalibacterium, which normalized before irC remission. These findings highlight the irC gut microbiota as functionally distinct but phylogenetically similar to non-irC and healthy microbiomes, with the exception of an acute, transient disruption early in irC. We underscore the significance of longitudinal microbiome profiling in developing clinical avenues to detect, monitor, and mitigate irC in ICI therapy cancer patients.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813286","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

A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis. STAG2-PAXIP1/PAGR1轴抑制肺肿瘤发生。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-09 DOI: 10.1084/jem.20240765

Emily L Ashkin, Yuning J Tang, Haiqing Xu, King L Hung, Julia A Belk, Hongchen Cai, Steven S Lopez, Deniz Nesli Dolcen, Jess D Hebert, Rui Li, Paloma A Ruiz, Tula Keal, Laura Andrejka, Howard Y Chang, Dmitri A Petrov, Jesse R Dixon, Zhichao Xu, Monte M Winslow

{"title":"A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis.","authors":"Emily L Ashkin, Yuning J Tang, Haiqing Xu, King L Hung, Julia A Belk, Hongchen Cai, Steven S Lopez, Deniz Nesli Dolcen, Jess D Hebert, Rui Li, Paloma A Ruiz, Tula Keal, Laura Andrejka, Howard Y Chang, Dmitri A Petrov, Jesse R Dixon, Zhichao Xu, Monte M Winslow","doi":"10.1084/jem.20240765","DOIUrl":"10.1084/jem.20240765","url":null,"abstract":"The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and showed that STAG2 is uniquely tumor-suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. STAG2 inactivation elicits changes in gene expression, chromatin accessibility, and 3D genome conformation that impact the cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relate STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin-mediated mechanisms of lung tumor suppression.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801073","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

Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis. 靶向 CD206+ 巨噬细胞会破坏关键抗肿瘤免疫轴的建立。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-27 DOI: 10.1084/jem.20240957

Arja Ray, Kenneth H Hu, Kelly Kersten, Tristan Courau, Nicholas F Kuhn, Itzia Zaleta-Linares, Bushra Samad, Alexis J Combes, Matthew F Krummel

{"title":"Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis.","authors":"Arja Ray, Kenneth H Hu, Kelly Kersten, Tristan Courau, Nicholas F Kuhn, Itzia Zaleta-Linares, Bushra Samad, Alexis J Combes, Matthew F Krummel","doi":"10.1084/jem.20240957","DOIUrl":"10.1084/jem.20240957","url":null,"abstract":"CD206 is a common marker of a putative immunosuppressive \"M2\" state in tumor-associated macrophages (TAMs). We made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs. Early depletion of CD206+ macrophages and monocytes (Mono/Macs) led to the indirect loss of conventional type I dendritic cells (cDC1), CD8 T cells, and NK cells in tumors. CD206+ TAMs robustly expressed CXCL9, contrasting with stress-responsive Spp1-expressing TAMs and immature monocytes, which became prominent with early depletion. CD206+ TAMs differentially attracted activated CD8 T cells, and the NK and CD8 T cells in CD206-depleted tumors were deficient in Cxcr3 and cDC1-supportive Xcl1 and Flt3l expressions. Disrupting this key antitumor axis decreased tumor control by antigen-specific T cells in mice. In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1, and NK signatures and was associated with better survival. These findings negate the unqualified classification of CD206+ \"M2-like\" macrophages as immunosuppressive.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142729266","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

Antiviral immunity lassoed down by excess RNA. 抗病毒免疫被过量的RNA束缚。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-06 DOI: 10.1084/jem.20241743

Erika Valeri, Anna Kajaste-Rudnitski

引用次数: 0

Terez Shea-Donohue: Optimism helps, and confidence in your work is critical. 特雷兹-谢-多诺霍乐观会有帮助，对自己的工作充满信心至关重要。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-10-08 DOI: 10.1084/jem.20241693

Montserrat Cols

引用次数: 0

Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer. 呼吸降低阻力：解决缺氧问题，克服肺癌免疫疗法障碍。