Nature Immunology最新文献_第4页

Simultaneous STING and lymphotoxin-β receptor activation induces B cell responses in tertiary lymphoid structures to potentiate antitumor immunity STING和淋巴毒素β受体同时激活可诱导三级淋巴结构中的B细胞反应，从而增强抗肿瘤免疫

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-09-02 DOI: 10.1038/s41590-025-02259-8

Junko Sawada, Yasuhiro Kikuchi, Maxwell Duah, Jose Luis Herrera, Fumiaki Kanamori, Krisztian Csomos, Tomoko Stansel, Nobuyoshi Hiraoka, Masayuki Yoshida, Jolan Walter, Carl F. Ware, Masanobu Komatsu

{"title":"Simultaneous STING and lymphotoxin-β receptor activation induces B cell responses in tertiary lymphoid structures to potentiate antitumor immunity","authors":"Junko Sawada, Yasuhiro Kikuchi, Maxwell Duah, Jose Luis Herrera, Fumiaki Kanamori, Krisztian Csomos, Tomoko Stansel, Nobuyoshi Hiraoka, Masayuki Yoshida, Jolan Walter, Carl F. Ware, Masanobu Komatsu","doi":"10.1038/s41590-025-02259-8","DOIUrl":"10.1038/s41590-025-02259-8","url":null,"abstract":"B cell-rich tertiary lymphoid structures (TLS) are associated with favorable prognosis and positive response to immunotherapy in cancer. Here we show that simultaneous activation of innate immune effectors, STING and lymphotoxin-β receptor (LTβR), results in CD8+ T cell-dependent tumor suppression while inducing high endothelial venule development and germinal center-like B cell responses in tumors to generate functional TLS in a T cell-dependent manner. In a neoadjuvant setting, activation of STING and LTβR by their agonists effectively immunized mice against tumor recurrence, leading to long-term survival. STING activation alone was insufficient for inducing B cell-containing TLS or eliciting long-term therapeutic effects. However, when combined with LTβR activation, it improved the fitness of TLS with B cell expansion and maturation to IgG-producing long-lived plasma cells and memory cells, increased CD4+ T cell recruitment and memory CD8+ T cell expansion, and shifted the TH2/TH17 balance, resulting in the potentiation of humoral and cellular immunity against tumors. These findings suggest a therapeutic approach of simultaneously activating STING and lymphotoxin pathways. Sawada et al. show simultaneous activation of the STING and lymphotoxin beta receptor signaling induces B cell-activating germinal center responses within tumor environment and enhances antitumor responses.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1766-1780"},"PeriodicalIF":27.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02259-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928013","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

Pre-TCR-targeted immunotherapy for T cell acute lymphoblastic leukemia T细胞急性淋巴细胞白血病的tcr前靶向免疫治疗

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-09-01 DOI: 10.1038/s41590-025-02265-w

Patricia Fuentes, Marina García-Peydró, Juan Alcain, Marta Mosquera, Carmela Cela, Claudia Cifuentes, Montserrat Torrebadell, Ignacio Isola, Mireia Camós, Manuel Ramírez, Balbino Alarcón, María L. Toribio

{"title":"Pre-TCR-targeted immunotherapy for T cell acute lymphoblastic leukemia","authors":"Patricia Fuentes, Marina García-Peydró, Juan Alcain, Marta Mosquera, Carmela Cela, Claudia Cifuentes, Montserrat Torrebadell, Ignacio Isola, Mireia Camós, Manuel Ramírez, Balbino Alarcón, María L. Toribio","doi":"10.1038/s41590-025-02265-w","DOIUrl":"10.1038/s41590-025-02265-w","url":null,"abstract":"Targeted immunotherapy for T cell acute lymphoblastic leukemia (T-ALL), an aggressive tumor of developing T cell progenitors, is an urgent unmet need, especially for relapsed/refractory disease. Selective T-ALL targeting is challenging due to the shared antigen expression between leukemic and normal T cells. Here we identify the pre-T cell receptor (pre-TCR), a surface receptor essential for T cell development, as a biomarker of leukemia-initiating cells (LICs) in human T-ALL. Loss-of-function genetic approaches demonstrate that pre-TCR signaling is necessary for LIC activity and tumor progression in pre-TCR+ T-ALL patient xenografts in mice. Furthermore, we demonstrate the specific therapeutic targeting of the pre-TCR with a monoclonal antibody against the invariant pTα subunit of the human pre-TCR, and validate an anti-pTα antibody–drug conjugate in vivo treatment as a potent immunotherapy for inhibiting LIC activity and tumor progression of T-ALL in mice. These findings reveal the suitability of pre-TCR targeting as a promising therapy for the treatment of individuals with relapsed/refractory T-ALL expressing the pre-TCR. The authors identify pre-TCR as a key biomarker and therapeutic target in T-ALL. Targeting it with an anti-pTα antibody–drug conjugate inhibits leukemia-initiating cells and tumor growth in mice, offering promise for relapsed/refractory T-ALL treatment.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1712-1725"},"PeriodicalIF":27.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02265-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923893","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

T cells in space and time T细胞在空间和时间上的变化

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-08-29 DOI: 10.1038/s41590-025-02274-9

Nicholas J. Bernard

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Antiphage SIR2 in humans 人类中的抗菌体SIR2

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-08-29 DOI: 10.1038/s41590-025-02271-y

Paula Jauregui

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E3 ligase RAD18 targets phosphorylated IRF3 to terminate IFNB1 transcription E3连接酶RAD18靶向磷酸化的IRF3以终止IFNB1转录

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-08-29 DOI: 10.1038/s41590-025-02256-x

Yiting Cai, Jiaqi Zheng, Linlin Zhao, Xue Wang, Lu Zhang, Jun Wang, Yuchuan Zhang, Rui Shi, Jin Han, Wei Han, Wei Chen

{"title":"E3 ligase RAD18 targets phosphorylated IRF3 to terminate IFNB1 transcription","authors":"Yiting Cai, Jiaqi Zheng, Linlin Zhao, Xue Wang, Lu Zhang, Jun Wang, Yuchuan Zhang, Rui Shi, Jin Han, Wei Han, Wei Chen","doi":"10.1038/s41590-025-02256-x","DOIUrl":"10.1038/s41590-025-02256-x","url":null,"abstract":"The transcription factor interferon regulatory factor 3 (IRF3) initiates type I interferon transcription, which is required for host defense. Here, we identify RAD18 as a central E3 ubiquitin ligase that selectively targets phosphorylated IRF3 (p-IRF3) for autophagic degradation. RAD18 specifically promotes the dissociation of p-IRF3 from the IFNB promoter and in turn terminates its transcriptional activity. Mechanistically, RAD18 binds the p-IRF3 dimer located on the IFNB promoter and triggers K63 polyubiquitylation of p-IRF3 at Lys 193. The ubiquitylated p-IRF3 dimer consequently dissociates from the IFNB promoter, translocates out of the nucleus and undergoes OPTN-mediated autophagic degradation. Rad18fl/fl Lysm-cre mice resist lethal vesicular stomatitis virus infection in vivo due to IFNβ overproduction. In H1N1-infected human macrophages or monocytes from individuals with active systemic lupus erythematosus, RAD18 protein levels negatively correlate with p-IRF3 and IFNB1 mRNA levels. Thus, RAD18 functions as a break to terminate IRF3-driven IFNB1 transcription and may be a potential therapeutic target for RNA virus infection or autoimmune diseases. IRF3 initiates type I IFN transcription, and this is required for host defense. Here, Chen and colleagues show that RAD18 terminates the transcriptional activity of IRF3 and subsequently promotes the autophagic degradation of IRF3.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 9","pages":"1581-1595"},"PeriodicalIF":27.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915635","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

LPS structure shapes Treg cells LPS结构塑造Treg细胞

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-08-29 DOI: 10.1038/s41590-025-02272-x

Stephanie Houston

引用次数: 0

Humanized mice for MS studies 用于MS研究的人源化小鼠

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-08-29 DOI: 10.1038/s41590-025-02273-w

Laurie A. Dempsey

引用次数: 0

Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis 人类肝脏和血液免疫细胞在脂肪肝疾病阶段的单细胞图谱揭示了与肝功能障碍和纤维化有关的独特特征

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-08-29 DOI: 10.1038/s41590-025-02255-y

Owen P. Martin, Michael S. Wallace, Christopher Oetheimer, Hailey B. Patel, Michael D. Butler, Lai Ping Wong, Pinzhu Huang, Joshua Elbaz, Charlotte Costentin, Shadi Salloum, Zoe Reinus, Adaeze Obinelo, Ulandt Kim, Stuti Shroff, Kathleen E. Corey, Yury V. Popov, Edgar D. Charles, Ruslan I. Sadreyev, Raymond T. Chung, Nadia Alatrakchi

{"title":"Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis","authors":"Owen P. Martin, Michael S. Wallace, Christopher Oetheimer, Hailey B. Patel, Michael D. Butler, Lai Ping Wong, Pinzhu Huang, Joshua Elbaz, Charlotte Costentin, Shadi Salloum, Zoe Reinus, Adaeze Obinelo, Ulandt Kim, Stuti Shroff, Kathleen E. Corey, Yury V. Popov, Edgar D. Charles, Ruslan I. Sadreyev, Raymond T. Chung, Nadia Alatrakchi","doi":"10.1038/s41590-025-02255-y","DOIUrl":"10.1038/s41590-025-02255-y","url":null,"abstract":"Immune cells play a central yet poorly understood role in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), a global cause of liver disease with limited treatment. Limited access to human livers and lack of studies across MASLD/MASH stages thwart identification of stage-specific immunological targets. Here we provide a unique single-cell RNA sequencing atlas of paired peripheral blood and liver fine-needle aspirates from a full-spectrum MASLD/MASH human cohort. Our findings included heightened immunoregulatory programs with MASH progression, such as enriched hepatic regulatory T cells, monocytic myeloid-derived suppressor cells, TREM2+S100A9+ macrophages and S100hiHLAlo type 2 conventional dendritic cells. Hepatic cytotoxic T cell functions increased with inflammation, but decreased with fibrosis, while acquiring an exhausted signature, whereas natural killer cell-driven toxicity intensified. Our dataset proposes immunological mechanisms for increased fibrogenesis and vulnerability to liver cancer and infections in MASH and provides a basis for a deeper understanding of human immunological dysfunction in chronic liver disease and a roadmap to new targeted therapies. Alatrakchi and colleagues profile immune cells from liver and blood obtained from patients with MASLD/MASH using single-cell sequencing. They note increased immunoregulatory programs that correlated with increased fibrogenesis and disease progression.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 9","pages":"1596-1611"},"PeriodicalIF":27.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915636","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

TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors 靶向共享β-连环蛋白突变的tcr工程T细胞可根除实体肿瘤

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-08-27 DOI: 10.1038/s41590-025-02252-1

Maria Stadheim Eggebø, Julia Heinzelbecker, Heyilimu Palashati, Nicholas Chandler, Trung The Tran, Yingqian Li, Weiwen Yang, Maarja Laos, Isaac Blaas, Even Holth Rustad, Ravi Chand Bollineni, Marina Delic-Sarac, Fridtjof Lund-Johansen, Morten Milek Nielsen, Johanna Olweus

{"title":"TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors","authors":"Maria Stadheim Eggebø, Julia Heinzelbecker, Heyilimu Palashati, Nicholas Chandler, Trung The Tran, Yingqian Li, Weiwen Yang, Maarja Laos, Isaac Blaas, Even Holth Rustad, Ravi Chand Bollineni, Marina Delic-Sarac, Fridtjof Lund-Johansen, Morten Milek Nielsen, Johanna Olweus","doi":"10.1038/s41590-025-02252-1","DOIUrl":"10.1038/s41590-025-02252-1","url":null,"abstract":"HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the CTNNB1S37F mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and HLA alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in >7,000 new cancer cases annually in the United States. T cell receptors (TCRs) that specifically recognize the mutant peptides were isolated from naive healthy donor T cells. T cells redirected with CTNNB1-S37F TCRs efficiently killed CTNNB1S37F+ cell lines and patient-derived organoids in vitro and eradicated established tumors in a melanoma cell line mouse model and a patient-derived xenograft model of endometrial adenocarcinoma naturally expressing the mutation and the restricting HLA. We propose that TCR-T cells targeting CTNNB1-S37F can serve as a basis for solid cancer immunotherapy. TCR-T cells are T cells engineered to express a specific T cell receptor. Here the authors present a TCR-T cell that targets CTNNB1-S37F, corresponding to a shared cancer driver mutation. This immunotherapy killed solid tumors when applied to a patient-derived xenograft model in mice.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1726-1736"},"PeriodicalIF":27.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02252-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906041","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

CRISPR screens identify STUB1 as an inhibitor of cytokine signaling in CD8+ T cells CRISPR筛选发现STUB1是CD8+ T细胞中细胞因子信号传导的抑制剂

IF 27.6 1区医学

Nature Immunology Pub Date : 2025-08-22 DOI: 10.1038/s41590-025-02247-y

引用次数: 0