Journal of Clinical Investigation最新文献

The saponin monophosphoryl lipid A nanoparticle adjuvant induces dose-dependent HIV vaccine responses in non-human primates.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-04 DOI: 10.1172/JCI185292

Parham Ramezani-Rad, Ester Marina-Zárate, Laura Maiorino, Amber Myers, Katarzyna Kaczmarek Michaels, Ivan S Pires, Nathaniel I Bloom, Mariane B Melo, Ashley A Lemnios, Paul G Lopez, Christopher A Cottrell, Iszac Burton, Bettina Groschel, Arpan Pradhan, Gabriela Stiegler, Magdolna Budai, Daniel Kumar, Sam Pallerla, Eddy Sayeed, Sangeetha L Sagar, Sudhir Pai Kasturi, Koen Ka Van Rompay, Lars Hangartner, Andreas Wagner, Dennis R Burton, William R Schief, Shane Crotty, Darrell J Irvine

{"title":"The saponin monophosphoryl lipid A nanoparticle adjuvant induces dose-dependent HIV vaccine responses in non-human primates.","authors":"Parham Ramezani-Rad, Ester Marina-Zárate, Laura Maiorino, Amber Myers, Katarzyna Kaczmarek Michaels, Ivan S Pires, Nathaniel I Bloom, Mariane B Melo, Ashley A Lemnios, Paul G Lopez, Christopher A Cottrell, Iszac Burton, Bettina Groschel, Arpan Pradhan, Gabriela Stiegler, Magdolna Budai, Daniel Kumar, Sam Pallerla, Eddy Sayeed, Sangeetha L Sagar, Sudhir Pai Kasturi, Koen Ka Van Rompay, Lars Hangartner, Andreas Wagner, Dennis R Burton, William R Schief, Shane Crotty, Darrell J Irvine","doi":"10.1172/JCI185292","DOIUrl":"https://doi.org/10.1172/JCI185292","url":null,"abstract":"The induction of durable protective immune responses is the main goal of prophylactic vaccines, and adjuvants play a role as drivers of such responses. Despite advances in vaccine strategies, a safe and effective HIV vaccine remains a significant challenge. The use of an appropriate adjuvant is crucial to the success of HIV vaccines. Here we assessed the saponin/MPLA nanoparticle (SMNP) adjuvant with an HIV envelope (Env) trimer, evaluating the safety and impact of multiple variables including adjuvant dose (16-fold dose range), immunization route, and adjuvant composition on the establishment of Env-specific memory T and B cell responses (TMem and BMem) and long-lived plasma cells in non-human primates (NHPs). Robust BMem were detected in all groups, but a 6-fold increase was observed in the highest SMNP dose group vs. the lowest dose group. Similarly, stronger vaccine responses were induced in the highest SMNP dose for CD40L+OX40+ CD4 TMem (11-fold), IFN-γ+ CD4 TMem (15-fold), IL21+ CD4 TMem (9-fold), circulating TFH (3.6-fold), bone marrow plasma cells (7-fold), and binding IgG (1.3-fold). Substantial tier-2 neutralizing antibodies were only observed in the higher SMNP dose groups. These investigations highlight the dose-dependent potency of SMNP in NHPs, which are relevant for human use and next-generation vaccines.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556935","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

Restoring mitochondrial function promotes hematopoietic reconstitution from cord blood following cryopreservation-related functional decline.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-04 DOI: 10.1172/JCI183607

Yaojin Huang, Xiaowei Xie, Mengyao Liu, Yawen Zhang, Junye Yang, Wenling Yang, Yu Hu, Saibing Qi, Yahui Feng, Guojun Liu, Shihong Lu, Xuemei Peng, Jinhui Ye, Shihui Ma, Jiali Sun, Lu Wang, Linping Hu, Lin Wang, Xiaofan Zhu, Hui Cheng, Zimin Sun, Junren Chen, Fang Dong, Yingchi Zhang, Tao Cheng

{"title":"Restoring mitochondrial function promotes hematopoietic reconstitution from cord blood following cryopreservation-related functional decline.","authors":"Yaojin Huang, Xiaowei Xie, Mengyao Liu, Yawen Zhang, Junye Yang, Wenling Yang, Yu Hu, Saibing Qi, Yahui Feng, Guojun Liu, Shihong Lu, Xuemei Peng, Jinhui Ye, Shihui Ma, Jiali Sun, Lu Wang, Linping Hu, Lin Wang, Xiaofan Zhu, Hui Cheng, Zimin Sun, Junren Chen, Fang Dong, Yingchi Zhang, Tao Cheng","doi":"10.1172/JCI183607","DOIUrl":"https://doi.org/10.1172/JCI183607","url":null,"abstract":"Umbilical cord blood (UCB) showcases substantial roles in hematopoietic stem cells (HSCs) transplantation and regenerative medicine. UCB is usually cryopreserved for years before use. Whether and how cryopreservation affects its function remain unclear. We constructed single-cell transcriptomic profile of CD34+ hematopoietic stem and progenitor cells (HSPCs) and mononuclear cells (MNCs) from fresh and cryopreserved UCB stored for 1-, 5-, 10-, and 19- years. Compared to fresh UCB, cryopreserved HSCs and multipotent progenitors (MPPs) exhibited more active cell cycle and lower HSC/MPP signature gene expressions. Hematopoietic reconstitution of cryopreserved HSPCs gradually decreased during the first 5 years but stabilized thereafter, aligning with the negative correlation between clinical neutrophil engraftment and cryopreservation duration of UCB. Cryopreserved HSPCs also showed reduced megakaryocyte generation. In contrast, cryopreserved natural killer (NK) cells and T cells maintained cytokine production and cytotoxic ability comparable to fresh cells. Mechanistically, cryopreserved HSPCs exhibited elevated reactive oxygen species, reduced ATP synthesis, and abnormal mitochondrial distribution, which collectively led to attenuated hematopoietic reconstitution. These effects could be ameliorated by sulforaphane. Together, we elucidated the negative impact of cryopreservation on UCB HSPCs and provided sulforaphane as a mitigation strategy, broadening the temporal window and scope for clinical applications of cryopreserved UCB. .","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556928","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

Patterns of autoantibody expression in multiple sclerosis identified through development of an autoantigen discovery technology.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-03 DOI: 10.1172/JCI171948

Europe B DiCillo, Evgueni Kountikov, Minghua Zhu, Stefan Lanker, Danielle E Harlow, Elizabeth R Piette, Weiguo Zhang, Brooke Hayward, Joshua Heuler, Julie Korich, Jeffrey L Bennett, David Pisetsky, Thomas Tedder

{"title":"Patterns of autoantibody expression in multiple sclerosis identified through development of an autoantigen discovery technology.","authors":"Europe B DiCillo, Evgueni Kountikov, Minghua Zhu, Stefan Lanker, Danielle E Harlow, Elizabeth R Piette, Weiguo Zhang, Brooke Hayward, Joshua Heuler, Julie Korich, Jeffrey L Bennett, David Pisetsky, Thomas Tedder","doi":"10.1172/JCI171948","DOIUrl":"https://doi.org/10.1172/JCI171948","url":null,"abstract":"Multiple sclerosis (MS) is a debilitating autoimmune disease of the CNS, which is characterized by demyelination and axonal injury and frequently preceded by a demyelinating event called clinically isolated syndrome (CIS). Despite the importance of B cells and autoantibodies in MS pathology, their target specificities remain largely unknown. For an agnostic and comprehensive evaluation of autoantibodies in MS, we developed and employed what we believe to be a novel autoantigen discovery technology, the Antigenome Platform. This Platform is a high-throughput assay comprising large-fragment (approximately 100 amino acids) cDNA libraries, phage display, serum antibody screening technology, and robust bioinformatics analysis pipelines. For autoantibody discovery, we assayed serum samples from CIS patients who received either placebo or treatment who were enrolled in the REFLEX clinical trial, which assessed the effects of IFN-β-1a (Rebif) clinical and MRI activity in patients with CIS. Serum autoantibodies from patients with CIS were significantly and reproducibly enriched for known and previously unreported protein targets; 166 targets were selected by over 10% of patients' sera. Further, 10 autoantibody biomarkers associated with disease activity and 17 associated with patient response to IFN-β-1a therapy. These findings indicate widespread autoantibody production in MS and provide biomarkers for continued study and prediction of disease progression.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542206","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

Basic science and translational implications of current knowledge on neuroendocrine tumors. 神经内分泌肿瘤现有知识的基础科学和转化意义。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-03 DOI: 10.1172/JCI186702

Lynnette Fernandez-Cuesta, Nicolas Alcala, Emilie Mathian, Jules Derks, Chrissie Thirlwell, Talya Dayton, Ilaria Marinoni, Aurel Perren, Thomas Walter, Matthieu Foll

{"title":"Basic science and translational implications of current knowledge on neuroendocrine tumors.","authors":"Lynnette Fernandez-Cuesta, Nicolas Alcala, Emilie Mathian, Jules Derks, Chrissie Thirlwell, Talya Dayton, Ilaria Marinoni, Aurel Perren, Thomas Walter, Matthieu Foll","doi":"10.1172/JCI186702","DOIUrl":"https://doi.org/10.1172/JCI186702","url":null,"abstract":"Neuroendocrine tumors (NETs) are a diverse group of malignancies that can occur in various organs, with a notable prevalence in the lungs and gastrointestinal tract, which are the focus of this Review. Although NETs are rare in individual organs, their incidence has increased over recent decades, highlighting the urgent need for current classification systems to evolve by incorporating recent advances in the understanding of NET biology. Several omics studies have revealed molecular subtypes, which, when integrated into existing classification frameworks, may provide more clinically relevant insights for patients with NETs. This Review examines recent progress in elucidating the biology of NETs, with a particular emphasis on the tumor microenvironment and cells of origin. The existence of different cells of origin, which may contribute to distinct molecular groups, along with profiles of immune infiltration - despite being generally low - could explain the emergence of more aggressive cases and the potential for metastatic progression. Given the molecular heterogeneity of NETs and the diversity of their microenvironments and different cells of origin, there is an urgent need to develop morphomolecular classification systems. Such systems would make it possible to better characterize tumor progression, identify new therapeutic targets, and, ultimately, guide the development of personalized therapies.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542195","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

Implications of gene × environment interactions in post-traumatic stress disorder risk and treatment.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-03 DOI: 10.1172/JCI185102

Carina Seah, Anne Elizabeth Sidamon-Eristoff, Laura M Huckins, Kristen J Brennand

{"title":"Implications of gene × environment interactions in post-traumatic stress disorder risk and treatment.","authors":"Carina Seah, Anne Elizabeth Sidamon-Eristoff, Laura M Huckins, Kristen J Brennand","doi":"10.1172/JCI185102","DOIUrl":"https://doi.org/10.1172/JCI185102","url":null,"abstract":"Exposure to traumatic stress is common in the general population. Variation in the brain's molecular encoding of stress potentially contributes to the heterogeneous clinical outcomes in response to traumatic experiences. For instance, only a minority of those exposed to trauma will develop post-traumatic stress disorder (PTSD). Risk for PTSD is at least partially heritable, with a growing number of genetic factors identified through GWAS. A major limitation of genetic studies is that they capture only the genetic component of risk, whereas PTSD by definition requires an environmental traumatic exposure. Furthermore, the extent, timing, and type of trauma affects susceptibility. Here, we discuss the molecular mechanisms of PTSD risk together with gene × environment interactions, with a focus on how either might inform genetic screening for individuals at high risk for disease, reveal biological mechanisms that might one day yield novel therapeutics, and impact best clinical practices even today. To close, we discuss the interaction of trauma with sex, gender, and race, with a focus on the implications for treatment. Altogether, we suggest that predicting, preventing, and treating PTSD will require integrating both genotypic and environmental information.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542204","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

Cathepsin K cleavage of Angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis. 在败血症中，血管生成素-2 的胰蛋白酶 K 分裂会产生有害的 Tie2 拮抗剂片段。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-03 DOI: 10.1172/JCI174135

Takashi Suzuki, Erik Loyde, Sara Chen, Valerie Etzrodt, Temitayo O Idowu, Amanda J Clark, Marie Christelle Saade, Brenda Mendoza Flores, Shulin Lu, Gabriel Birrane, Vamsidhara Vemireddy, Benjamin Seeliger, Sascha David, Samir M Parikh

{"title":"Cathepsin K cleavage of Angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis.","authors":"Takashi Suzuki, Erik Loyde, Sara Chen, Valerie Etzrodt, Temitayo O Idowu, Amanda J Clark, Marie Christelle Saade, Brenda Mendoza Flores, Shulin Lu, Gabriel Birrane, Vamsidhara Vemireddy, Benjamin Seeliger, Sascha David, Samir M Parikh","doi":"10.1172/JCI174135","DOIUrl":"https://doi.org/10.1172/JCI174135","url":null,"abstract":"Elevated Angiopoietin-2 is associated with diverse inflammatory conditions including sepsis, a leading global cause of mortality. During inflammation, Angiopoietin-2 antagonizes the endothelium-enriched receptor Tie2 to destabilize the vasculature. In other contexts, Angiopoietin-2 stimulates Tie2. The basis for context-dependent antagonism remains incompletely understood. Here we show that inflammation-induced proteolytic cleavage of Angiopoietin-2 converts this ligand from Tie2 agonist to antagonist. Conditioned media from stimulated macrophages induced endothelial Angiopoietin-2 secretion. Unexpectedly, this was associated with reduction of the 75 kDa full-length protein and appearance of new 25 and 50 kDa C-terminal fragments. Peptide sequencing proposed cathepsin K as a candidate protease. Cathepsin K was necessary and sufficient to cleave Angiopoietin-2. Recombinant 25 and 50 kDa Angiopoietin-2 fragments (cANGPT225, cANGPT250) bound and antagonized Tie2. Cathepsin K inhibition with the Phase-3 small molecule inhibitor odanacatib improved survival in distinct murine sepsis models. Full-length Angiopoietin-2 enhanced survival in endotoxemic mice administered odanacatib and, conversely, increased mortality in the drug's absence. Odanacatib's benefit was reversed by heterologous cANGPT225. Septic humans accumulated circulating Angiopoietin-2 fragments, which were associated with adverse outcomes. These results identify cathepsin K as a candidate marker of sepsis and a proteolytic mechanism for the conversion of Angiopoietin-2 from Tie2 agonist to antagonist with therapeutic implications for inflammatory conditions associated with Angiopoietin-2 induction.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542134","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

Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-03 DOI: 10.1172/JCI188942

Qianqian Ge, Jiachao Yang, Fei Huang, Xinyue Dai, Chao Chen, Jingxin Guo, Mi Wang, Mengyue Zhu, Yijie Shao, Yuxian Xia, Yu Zhou, Jieqiao Peng, Suixin Deng, Jiachen Shi, Yiqi Hu, Huiying Zhang, Yi Wang, Xiaoqun Wang, Xiao-Ming Li, Zhong Chen, Yousheng Shu, Jun-Ming Zhu, Jianmin Zhang, Ying Shen, Shumin Duan, Shengjin Xu, Li Shen, Jiadong Chen

{"title":"Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy.","authors":"Qianqian Ge, Jiachao Yang, Fei Huang, Xinyue Dai, Chao Chen, Jingxin Guo, Mi Wang, Mengyue Zhu, Yijie Shao, Yuxian Xia, Yu Zhou, Jieqiao Peng, Suixin Deng, Jiachen Shi, Yiqi Hu, Huiying Zhang, Yi Wang, Xiaoqun Wang, Xiao-Ming Li, Zhong Chen, Yousheng Shu, Jun-Ming Zhu, Jianmin Zhang, Ying Shen, Shumin Duan, Shengjin Xu, Li Shen, Jiadong Chen","doi":"10.1172/JCI188942","DOIUrl":"https://doi.org/10.1172/JCI188942","url":null,"abstract":"The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult to determine the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA-seq approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2, and NFKBIA, which associate with mTOR pathway, inflammatory response, and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, γ-H2AX, and β-Gal, and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of patients with drug-resistant epilepsy with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent marker expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and what we believe to be new insights into the pathophysiological mechanisms of drug-resistant epilepsy.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542205","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

Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis. 内皮 OX40 激活可通过 S1P/YAP 介导的血管生成促进肿瘤细胞摆脱 T 细胞的监控。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-03 DOI: 10.1172/JCI186291

Baoyu He, Rou Zhao, Baogui Zhang, Hongli Pan, Jilan Liu, Lunhua Huang, Yingying Wei, Dong Yang, Jing Liang, Mingyi Wang, Mingsheng Zhao, Sen Wang, Fengyun Dong, Junfeng Zhang, Yanhua Zhang, Xu Zhang, Xiao Zhang, Guanjun Dong, Huabao Xiong, Qingli Bie, Bin Zhang

{"title":"Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis.","authors":"Baoyu He, Rou Zhao, Baogui Zhang, Hongli Pan, Jilan Liu, Lunhua Huang, Yingying Wei, Dong Yang, Jing Liang, Mingyi Wang, Mingsheng Zhao, Sen Wang, Fengyun Dong, Junfeng Zhang, Yanhua Zhang, Xu Zhang, Xiao Zhang, Guanjun Dong, Huabao Xiong, Qingli Bie, Bin Zhang","doi":"10.1172/JCI186291","DOIUrl":"https://doi.org/10.1172/JCI186291","url":null,"abstract":"Understanding the complexity of the tumor microenvironment is vital for improving immunotherapy outcomes. Here, we report that the T cell costimulatory molecule OX40 was highly expressed in tumor endothelial cells (ECs) and was negatively associated with the prognosis of patients, which is irrelevant to T cell activation. Analysis of conditional OX40 loss- and gain-of-function transgenic mice showed that OX40 signal in ECs counteracted the antitumor effects produced in T cells by promoting angiogenesis. Mechanistically, leucine-rich repeat-containing GPCR5 (Lgr5+ ) cancer stem cells induced OX40 expression in tumor ECs via EGF/STAT3 signaling. Activated OX40 interacted with Spns lysolipid transporter 2 (Spns2), obstructing the export of sphingosine 1-phosphate (S1P) and resulting in S1P intracellular accumulation. Increased S1P directly bound to Yes 1-associated protein (YAP), disrupting its interaction with large tumor suppressor kinase 1 (LATS1) and promoting YAP nuclear translocation. Finally, the YAP inhibitor verteporfin enhanced the antitumor effects of the OX40 agonist. Together, these findings reveal an unexpected protumor role of OX40 in ECs, highlighting the effect of nonimmune cell compartments on immunotherapy.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542202","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

Zombie neurons in epilepsy: a burgeoning role for senescence in drug-resistant epilepsy.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-03 DOI: 10.1172/JCI189519

Gemma L Carvill

引用次数: 0

Bridging the gap: insights into sensorimotor deficits in NMDA receptor antibody encephalitis.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-03-03 DOI: 10.1172/JCI188251

Puneet Opal, Geoffrey T Swanson

引用次数: 0