Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death worldwide, with plaque instability being a major culprit. Phenotypic switching of vascular smooth muscle cells (VSMCs) is a central event in atherosclerosis, driving both plaque progression and stability, yet the underlying mechanisms are incompletely understood, limiting drug development targeting this process. Kinesin family member 13B (KIF13B) has been implicated in vascular biology, but its function in VSMCs is unknown. Here, we demonstrate that VSMC-specific deletion of Kif13b in mice overexpressing proprotein convertase subtilisin/kexin type 9 (PCSK9) exacerbates lesion development and impairs plaque stability, characterized by thinner fibrous caps and increased inflammation. Mechanistically, we identified that KIF13B facilitates the ubiquitination and proteasomal degradation of Krüppel-like factor 4 (KLF4) through the Potassium channel tetramerization domain containing 10 (KCTD10)-dependent pathway. This KIF13B/KCTD10 axis reduces KLF4 protein levels, thereby inhibiting the pro-inflammatory responses and fibroblast-like transition of VSMCs to preserve their contractile phenotype. Importantly, the adverse effects of Kif13b deficiency on atherogenesis were effectively rescued by the small-molecule KLF4 inhibitor Kenpaullone. Our results unveil a VSMC-specific atheroprotective role for KIF13B, define the KIF13B/KCTD10/KLF4 pathway as a key regulatory axis governing VSMC fate and plaque stability, and validate its therapeutic potential for treating advanced atherosclerosis.
{"title":"Vascular smooth muscle cell-derived KIF13B protects against atherosclerosis: evidence from humans and mice.","authors":"Guolin Miao,Yufei Han,Jingxuan Chen,Yiran Liu,Ge Zhang,Shaotong Pei,Yinqi Zhao,Yitong Xu,Liwen Zheng,Zhaoling Li,Xiangru Liu,Sijing Shi,Xuya Kang,Yahan Liu,Ling Zhang,Wei Huang,Yuhui Wang,Junnan Tang,Erdan Dong,Xunde Xian","doi":"10.1172/jci194175","DOIUrl":"https://doi.org/10.1172/jci194175","url":null,"abstract":"Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death worldwide, with plaque instability being a major culprit. Phenotypic switching of vascular smooth muscle cells (VSMCs) is a central event in atherosclerosis, driving both plaque progression and stability, yet the underlying mechanisms are incompletely understood, limiting drug development targeting this process. Kinesin family member 13B (KIF13B) has been implicated in vascular biology, but its function in VSMCs is unknown. Here, we demonstrate that VSMC-specific deletion of Kif13b in mice overexpressing proprotein convertase subtilisin/kexin type 9 (PCSK9) exacerbates lesion development and impairs plaque stability, characterized by thinner fibrous caps and increased inflammation. Mechanistically, we identified that KIF13B facilitates the ubiquitination and proteasomal degradation of Krüppel-like factor 4 (KLF4) through the Potassium channel tetramerization domain containing 10 (KCTD10)-dependent pathway. This KIF13B/KCTD10 axis reduces KLF4 protein levels, thereby inhibiting the pro-inflammatory responses and fibroblast-like transition of VSMCs to preserve their contractile phenotype. Importantly, the adverse effects of Kif13b deficiency on atherogenesis were effectively rescued by the small-molecule KLF4 inhibitor Kenpaullone. Our results unveil a VSMC-specific atheroprotective role for KIF13B, define the KIF13B/KCTD10/KLF4 pathway as a key regulatory axis governing VSMC fate and plaque stability, and validate its therapeutic potential for treating advanced atherosclerosis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huai-Chia Chuang,Chia-Wen Wang,Chia-Hsin Hsueh,Yu-Zhi Xiao,Ching-Yi Tsai,Pu-Ming Hsu,Evelyn L Tan,Hsien-Yi Chiu,Tse-Hua Tan
MAP kinase kinase kinase kinase (MAP4K) family kinases are key kinases for T-cell-mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. Using T-cell-specific Map4k2 conditional knockout (T-Map4k2 cKO) mice, single-cell RNA sequencing (scRNA-seq), and mass spectrometry analysis, we found that MAP4K2 interacted with DDX39B, induced forkhead box protein P3 (FOXP3) gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39B, leading to DDX39B nuclear translocation and subsequent Foxp3 RNA splicing. MAP4K2-induced FOXP3 mRNA levels were abolished in DDX39B knockout T cells. Furthermore, T-Map4k2 cKO mice displayed the reduction of Treg population and the sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti-PD-1 immunotherapeutic effect on pancreatic cancer was significantly improved in T-Map4k2 cKO mice, Treg-specific Map4k2-deficient mice, adoptively transferred chimeric mice, or MAP4K2-inhibitor-treated mice. Consistently, scRNA-seq analysis of human pancreatic patients showed increased MAP4K2 levels in infiltrating Treg cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39B nuclear translocation, leading to the attenuation of antitumor immunity.
{"title":"MAP4K2 suppresses antitumor immunity in a pancreatic cancer model by promoting Treg differentiation.","authors":"Huai-Chia Chuang,Chia-Wen Wang,Chia-Hsin Hsueh,Yu-Zhi Xiao,Ching-Yi Tsai,Pu-Ming Hsu,Evelyn L Tan,Hsien-Yi Chiu,Tse-Hua Tan","doi":"10.1172/jci196379","DOIUrl":"https://doi.org/10.1172/jci196379","url":null,"abstract":"MAP kinase kinase kinase kinase (MAP4K) family kinases are key kinases for T-cell-mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. Using T-cell-specific Map4k2 conditional knockout (T-Map4k2 cKO) mice, single-cell RNA sequencing (scRNA-seq), and mass spectrometry analysis, we found that MAP4K2 interacted with DDX39B, induced forkhead box protein P3 (FOXP3) gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39B, leading to DDX39B nuclear translocation and subsequent Foxp3 RNA splicing. MAP4K2-induced FOXP3 mRNA levels were abolished in DDX39B knockout T cells. Furthermore, T-Map4k2 cKO mice displayed the reduction of Treg population and the sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti-PD-1 immunotherapeutic effect on pancreatic cancer was significantly improved in T-Map4k2 cKO mice, Treg-specific Map4k2-deficient mice, adoptively transferred chimeric mice, or MAP4K2-inhibitor-treated mice. Consistently, scRNA-seq analysis of human pancreatic patients showed increased MAP4K2 levels in infiltrating Treg cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39B nuclear translocation, leading to the attenuation of antitumor immunity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"282 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Were R Omange,Benjamin D Varco-Merth,Omo Fadeyi,Alejandra Marenco,Hiroshi Takata,Derick M Duell,William D Goodwin,Paula Armitage,Christine M Fennessey,Emek Kose,Taina T Immonen,Ewelina Kosmider,William J Bosche,Randy Fast,Chris Homick,Kelli Oswald,Rebecca Shoemaker,Rachele Bochart,Rhonda MacAllister,Caralyn S Labriola,Jeremy V Smedley,Michael K Axthelm,Paul T Edlefsen,Brandon F Keele,Jeffrey D Lifson,Janina Gergen,Benjamin Petsch,Susanne Rauch,Louis J Picker,Afam A Okoye
HIV/SIV-specific CD8+ T cell responses are typically unable to control viral rebound following antiretroviral therapy (ART) interruption (ATI). To investigate whether enhancing the magnitude and activation of SIV-specific CD8+ T cells at the time of ATI can improve the immune interception of reactivating SIV infections we vaccinated SIVmac239-infected rhesus macaques (RMs) on ART, boosting immediately prior to ATI, with a nucleoside-unmodified mRNA vaccine expressing SIVmac239 Gag (mRNA/SIVgag) alone or in combination with Nef (mRNA/SIVnef) and Pol (mRNA/SIVpol). The mRNA/SIVgag vaccine was effective in boosting Gag-specific CD8+ T cells in blood and lymphoid tissues. Following ATI, the mRNA/SIV-Gag vaccine group showed a significant delay in time to measurable viral rebound compared to controls, and manifested lower plasma viral loads (PVL) for up to 6 weeks after rebound. Similarly, RMs that received mRNA/SIVgag, mRNA/SIVnef, and mRNA/SIVpol also manifested a delay in SIV rebound compared to controls, suggesting that boosting SIV-specific CD8+ T cells during ATI can enhance early immune targeting of reactivating SIV infections. However, viral control was not sustained long-term as PVLs were similar across vaccinees and controls by 24 weeks post-rebound, highlighting the need for adjunctive therapies to improve the durability of virologic control elicited by CD8+ T cell-targeting vaccines.
{"title":"Boosting SIV-specific CD8+ T cell responses prior to ART interruption extends time to SIVmac239 rebound.","authors":"Were R Omange,Benjamin D Varco-Merth,Omo Fadeyi,Alejandra Marenco,Hiroshi Takata,Derick M Duell,William D Goodwin,Paula Armitage,Christine M Fennessey,Emek Kose,Taina T Immonen,Ewelina Kosmider,William J Bosche,Randy Fast,Chris Homick,Kelli Oswald,Rebecca Shoemaker,Rachele Bochart,Rhonda MacAllister,Caralyn S Labriola,Jeremy V Smedley,Michael K Axthelm,Paul T Edlefsen,Brandon F Keele,Jeffrey D Lifson,Janina Gergen,Benjamin Petsch,Susanne Rauch,Louis J Picker,Afam A Okoye","doi":"10.1172/jci198294","DOIUrl":"https://doi.org/10.1172/jci198294","url":null,"abstract":"HIV/SIV-specific CD8+ T cell responses are typically unable to control viral rebound following antiretroviral therapy (ART) interruption (ATI). To investigate whether enhancing the magnitude and activation of SIV-specific CD8+ T cells at the time of ATI can improve the immune interception of reactivating SIV infections we vaccinated SIVmac239-infected rhesus macaques (RMs) on ART, boosting immediately prior to ATI, with a nucleoside-unmodified mRNA vaccine expressing SIVmac239 Gag (mRNA/SIVgag) alone or in combination with Nef (mRNA/SIVnef) and Pol (mRNA/SIVpol). The mRNA/SIVgag vaccine was effective in boosting Gag-specific CD8+ T cells in blood and lymphoid tissues. Following ATI, the mRNA/SIV-Gag vaccine group showed a significant delay in time to measurable viral rebound compared to controls, and manifested lower plasma viral loads (PVL) for up to 6 weeks after rebound. Similarly, RMs that received mRNA/SIVgag, mRNA/SIVnef, and mRNA/SIVpol also manifested a delay in SIV rebound compared to controls, suggesting that boosting SIV-specific CD8+ T cells during ATI can enhance early immune targeting of reactivating SIV infections. However, viral control was not sustained long-term as PVLs were similar across vaccinees and controls by 24 weeks post-rebound, highlighting the need for adjunctive therapies to improve the durability of virologic control elicited by CD8+ T cell-targeting vaccines.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"143 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria C Foss-Freitas,Donatella Gilio,Lynn Pais,Eric D Buras,Romil Kaul Verma,Melanie O'Leary,Heidi L Rehm,Carmen Glaze,Kathryn Russell,Andre Monteiro da Rocha,Adam Neidert,Patrick Seale,Miriam S Udler,Elif A Oral,Tae-Hwa Chun
Lipodystrophy syndromes are marked by loss of adipose tissue (AT), which leads to insulin resistance and metabolic syndrome development. We identified a heterozygous nonsense variant in early B cell factor 2 (EBF2) (Chr8:26033143C>A, NM_022659.4: c.493G>T, p.E165X) in a patient with atypical partial lipodystrophy (PLD). The EBF family is crucial for the differentiation and function of various mesenchymal tissues. Through in vitro and in vivo disease models, we discovered that this variant limits adipocyte differentiation and hampers adipose tissue remodeling. Heterozygous knock-in (Ebf2E165X/+) mice showed restricted adipogenesis and defective extracellular matrix (ECM) remodeling during post-weaning and high-fat diet (HFD)-induced adipose tissue expansion. HFD caused abnormal adipocyte hypertrophy, decreased expression of adiponectin and leptin, and glucose intolerance in Ebf2E165X/+ mice. Furthermore, key mitochondrial genes involved in fatty acid metabolism and oxidation were specifically downregulated in the Ebf2E165X/+ adipose tissue. Our results suggest that EBF2 dysfunction driven by this nonsense variant drives disease pathology, establishing a connection between EBF2 disruption and an atypical form of lipodystrophy.
脂肪营养不良综合征的特征是脂肪组织（AT）的损失，这导致胰岛素抵抗和代谢综合征的发展。我们在非典型部分脂肪营养不良（PLD）患者中发现了早期B细胞因子2 （EBF2）的杂合无义变异（Chr8:26033143C> a, NM_022659.4: c.493G>T, p.E165X）。EBF家族对各种间质组织的分化和功能至关重要。通过体外和体内疾病模型，我们发现这种变异限制了脂肪细胞的分化，阻碍了脂肪组织的重塑。杂合子敲入（Ebf2E165X/+）小鼠在断奶后和高脂饮食（HFD）诱导的脂肪组织扩张过程中表现出脂肪生成受限和细胞外基质（ECM）重塑缺陷。HFD引起Ebf2E165X/+小鼠脂肪细胞异常肥大，脂联素和瘦素表达降低，葡萄糖耐受不良。此外，参与脂肪酸代谢和氧化的关键线粒体基因在Ebf2E165X/+脂肪组织中特异性下调。我们的研究结果表明，由这种无义变异驱动的EBF2功能障碍驱动疾病病理，建立了EBF2破坏与非典型脂肪营养不良之间的联系。
{"title":"EBF2 variant identified in a patient with atypical partial lipodystrophy causes adipose fibrosis and dysfunction.","authors":"Maria C Foss-Freitas,Donatella Gilio,Lynn Pais,Eric D Buras,Romil Kaul Verma,Melanie O'Leary,Heidi L Rehm,Carmen Glaze,Kathryn Russell,Andre Monteiro da Rocha,Adam Neidert,Patrick Seale,Miriam S Udler,Elif A Oral,Tae-Hwa Chun","doi":"10.1172/jci192737","DOIUrl":"https://doi.org/10.1172/jci192737","url":null,"abstract":"Lipodystrophy syndromes are marked by loss of adipose tissue (AT), which leads to insulin resistance and metabolic syndrome development. We identified a heterozygous nonsense variant in early B cell factor 2 (EBF2) (Chr8:26033143C>A, NM_022659.4: c.493G>T, p.E165X) in a patient with atypical partial lipodystrophy (PLD). The EBF family is crucial for the differentiation and function of various mesenchymal tissues. Through in vitro and in vivo disease models, we discovered that this variant limits adipocyte differentiation and hampers adipose tissue remodeling. Heterozygous knock-in (Ebf2E165X/+) mice showed restricted adipogenesis and defective extracellular matrix (ECM) remodeling during post-weaning and high-fat diet (HFD)-induced adipose tissue expansion. HFD caused abnormal adipocyte hypertrophy, decreased expression of adiponectin and leptin, and glucose intolerance in Ebf2E165X/+ mice. Furthermore, key mitochondrial genes involved in fatty acid metabolism and oxidation were specifically downregulated in the Ebf2E165X/+ adipose tissue. Our results suggest that EBF2 dysfunction driven by this nonsense variant drives disease pathology, establishing a connection between EBF2 disruption and an atypical form of lipodystrophy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"193 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Freja Herborg,Lisa K Konrad,Søren H Jørgensen,Jamila H Lilja,Benoît Delignat-Lavaud,Leonie P Posselt,Ciara F Pugh,Sofie A Bach,Cecilia F Ratner,Nora Awadallah,Jose A Pino,Frida Berlin,Aske L Ejdrup,Mikkel V Olesen,Mattias Rickhag,Birgitte Holst,Susana Aznar,Felix P Mayer,David Woldbye,Gonzalo E Torres,Louis-Eric Trudeau,Ulrik Gether
Atypical dopamine transporter (DAT) deficiency syndrome (DTDS) arises from genetic disruption of DAT function and is characterized by early-onset parkinsonism alongside comorbid psychiatric symptoms. However, the underlying pathobiological processes are largely unknown. Here, we present a mouse model of atypical DTDS based on the patient-derived compound heterozygote genotype, DAT-I312F/D421N+/+. DAT-I312F/D421N+/+ mice exhibited markedly impaired DAT function, leading to widespread changes in dopamine homeostasis, including elevated extracellular dopamine levels, reduced tyrosine hydroxylase and dopamine D1/D2 receptor expression, and decreased evoked dopamine release, mechanistically linked to enhanced tonic D2 autoreceptor inhibition. Fiber photometry measurements revealed disrupted fast striatal dopamine release dynamics, while confocal imaging showed reduced striatal dopaminergic axon fiber density. These neurochemical changes were accompanied by a psychomotor phenotype characterized by hyperlocomotion, enhanced exploration and pronounced clasping. Both amphetamine and anticholinergic treatment ameliorated the aberrant hyperactivity. Notably, amphetamine-induced dopamine release was profoundly blunted in ventral striatum but largely preserved in dorsal striatum, implicating region-specific dopamine release dynamics as a determinant of divergent behavioral and pharmacological responses. Summarized, our findings uncover multiscale dopamine dysfunction that links presynaptic DAT impairment to synaptic and circuit-level disruptions, offering insight into atypical DTDS and the co-occurrence of movement and psychiatric features.
{"title":"Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and ADHD.","authors":"Freja Herborg,Lisa K Konrad,Søren H Jørgensen,Jamila H Lilja,Benoît Delignat-Lavaud,Leonie P Posselt,Ciara F Pugh,Sofie A Bach,Cecilia F Ratner,Nora Awadallah,Jose A Pino,Frida Berlin,Aske L Ejdrup,Mikkel V Olesen,Mattias Rickhag,Birgitte Holst,Susana Aznar,Felix P Mayer,David Woldbye,Gonzalo E Torres,Louis-Eric Trudeau,Ulrik Gether","doi":"10.1172/jci169297","DOIUrl":"https://doi.org/10.1172/jci169297","url":null,"abstract":"Atypical dopamine transporter (DAT) deficiency syndrome (DTDS) arises from genetic disruption of DAT function and is characterized by early-onset parkinsonism alongside comorbid psychiatric symptoms. However, the underlying pathobiological processes are largely unknown. Here, we present a mouse model of atypical DTDS based on the patient-derived compound heterozygote genotype, DAT-I312F/D421N+/+. DAT-I312F/D421N+/+ mice exhibited markedly impaired DAT function, leading to widespread changes in dopamine homeostasis, including elevated extracellular dopamine levels, reduced tyrosine hydroxylase and dopamine D1/D2 receptor expression, and decreased evoked dopamine release, mechanistically linked to enhanced tonic D2 autoreceptor inhibition. Fiber photometry measurements revealed disrupted fast striatal dopamine release dynamics, while confocal imaging showed reduced striatal dopaminergic axon fiber density. These neurochemical changes were accompanied by a psychomotor phenotype characterized by hyperlocomotion, enhanced exploration and pronounced clasping. Both amphetamine and anticholinergic treatment ameliorated the aberrant hyperactivity. Notably, amphetamine-induced dopamine release was profoundly blunted in ventral striatum but largely preserved in dorsal striatum, implicating region-specific dopamine release dynamics as a determinant of divergent behavioral and pharmacological responses. Summarized, our findings uncover multiscale dopamine dysfunction that links presynaptic DAT impairment to synaptic and circuit-level disruptions, offering insight into atypical DTDS and the co-occurrence of movement and psychiatric features.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Johnathan R Kent,Keene L Abbott,Rachel Nordgren,Amy Deik,Nupur K Das,Millenia Waite,Tenzin Kunchok,Anna Shevzov-Zebrun,Nathaniel Christiansen,Amir Sadek,Darren S Bryan,Mark K Ferguson,Jessica S Donington,Alexander Muir,Yatrik M Shah,Clary B Clish,Matthew G Vander Heiden,Maria Lucia L Madariaga,Peggy P Hsu
{"title":"Intraoperative arteriovenous patient sampling to assess in situ non-small cell lung cancer metabolism.","authors":"Johnathan R Kent,Keene L Abbott,Rachel Nordgren,Amy Deik,Nupur K Das,Millenia Waite,Tenzin Kunchok,Anna Shevzov-Zebrun,Nathaniel Christiansen,Amir Sadek,Darren S Bryan,Mark K Ferguson,Jessica S Donington,Alexander Muir,Yatrik M Shah,Clary B Clish,Matthew G Vander Heiden,Maria Lucia L Madariaga,Peggy P Hsu","doi":"10.1172/jci198821","DOIUrl":"https://doi.org/10.1172/jci198821","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"293 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yongxia Wu,Linlu Tian,Allison Pugel,Reza Alimohammadi,Qiao Cheng,Weiguo Cui,Michael I Nishimura,Lauren E Ball,Chien-Wei Lin,Shikhar Mehrotra,Andrew S Kraft,Xue-Zhong Yu
The PIM kinase family is critically involved in tumorigenesis, yet its role in primary T cells is understudied. We reported that PIM2, distinct from the other two isoforms, inhibits T-cell responses to alloantigen. Here, we further established PIM2 as a key negative regulator in anti-tumor immunity. Pim2 deficiency in tumor antigen-specific or polyclonal T cells enhanced their ability to control tumor growth in murine breast cancer, melanoma and leukemia models. Pim2 deficiency enhanced cytokine production and metabolic activities in tumor-infiltrating CD8 T cells. Pim2 deficiency increased TCF1 expression and memory-like phenotype in CD8 T cells from lymphoid organs. Mechanistically, PIM2 facilitated LC3 lipidation, P62 degradation and autophagic flux in T cells, leading to impaired glycolysis and effector cytokine production. Furthermore, through modulating VPRBP kinase phosphorylation, PIM2 inhibited histone methyltransferase activity of EZH2 in CD8 T cells, causing disrupted memory-like phenotype. Notably, the PIM2 inhibitor JP11646 markedly enhanced antitumor T-cell response. The immunosuppressive role of PIM2 was validated in human T cells, where inhibition of PIM2 enhanced antitumor responses in engineered human T cells including melanoma-specific TCR-T cells and CD19CAR-T cells. Collectively, PIM2 represents a promising target for improving cancer immunotherapy through enhancing effector differentiation and persistence of CD8 T cells.
{"title":"Targeting Pim2 Improves Antitumor Immunity through Promoting Effector Function and Persistence of CD8 T cells.","authors":"Yongxia Wu,Linlu Tian,Allison Pugel,Reza Alimohammadi,Qiao Cheng,Weiguo Cui,Michael I Nishimura,Lauren E Ball,Chien-Wei Lin,Shikhar Mehrotra,Andrew S Kraft,Xue-Zhong Yu","doi":"10.1172/jci192928","DOIUrl":"https://doi.org/10.1172/jci192928","url":null,"abstract":"The PIM kinase family is critically involved in tumorigenesis, yet its role in primary T cells is understudied. We reported that PIM2, distinct from the other two isoforms, inhibits T-cell responses to alloantigen. Here, we further established PIM2 as a key negative regulator in anti-tumor immunity. Pim2 deficiency in tumor antigen-specific or polyclonal T cells enhanced their ability to control tumor growth in murine breast cancer, melanoma and leukemia models. Pim2 deficiency enhanced cytokine production and metabolic activities in tumor-infiltrating CD8 T cells. Pim2 deficiency increased TCF1 expression and memory-like phenotype in CD8 T cells from lymphoid organs. Mechanistically, PIM2 facilitated LC3 lipidation, P62 degradation and autophagic flux in T cells, leading to impaired glycolysis and effector cytokine production. Furthermore, through modulating VPRBP kinase phosphorylation, PIM2 inhibited histone methyltransferase activity of EZH2 in CD8 T cells, causing disrupted memory-like phenotype. Notably, the PIM2 inhibitor JP11646 markedly enhanced antitumor T-cell response. The immunosuppressive role of PIM2 was validated in human T cells, where inhibition of PIM2 enhanced antitumor responses in engineered human T cells including melanoma-specific TCR-T cells and CD19CAR-T cells. Collectively, PIM2 represents a promising target for improving cancer immunotherapy through enhancing effector differentiation and persistence of CD8 T cells.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"108 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glioblastoma (GBM) is a highly lethal brain tumor with limited treatment options and resistance to immune checkpoint inhibitors due to its immunosuppressive tumor microenvironment (TME). Here, we identify OLIG2 as a key regulator of immune evasion in GBM stem-like cells, inhibiting CD8+ T cell-dependent antitumor immunity, while promoting pro-tumor macrophages polarization. Mechanistically, OLIG2 recruits HDAC7 to repress CXCL10 transcription, inducing STAT3 activation in tumor-associated macrophages (TAMs) and decreasing CD8+ T cell infiltration and activation. Genetic deletion of OLIG2 significantly increases CXCL10 secretion, shifting TAMs toward an anti-tumor phenotype and enhancing CD8+ T cell activities. Furthermore, upregulated OLIG2 expression is correlated to resistance to immune checkpoint inhibitors (ICIs) in GBM patients. OLIG2 inhibition by either genetic deficiency or pharmacological targeting with CT-179 sensitizes GBM tumors to anti-PD-L1 therapy, enhancing antitumor immune responses and prolonging survival. Our findings reveal OLIG2+ glioma stem-like cells as critical mediators of immune evasion and identify the OLIG2/HDAC7/CXCL10 axis as a potential therapeutic target to enhance immune checkpoint inhibitors efficacy and to improve immunotherapy outcomes in aggressive GBM.
{"title":"Oligodendrocyte transcription factor 2 orchestrates glioblastoma immune evasion by suppressing CXCL10 and CD8+ T cell activation.","authors":"Xinchun Zhang,Jinjiang Xue,Cunyan Zhao,Chenqiuyue Zeng,Jiacheng Zhong,Gangfeng Yu,Xi Yang,Yao Ling,Dazhen Li,Jiaxiao Yang,Yun Xiu,Hongda Li,Shiyuan Hong,Liangjun Qiao,Song Chen,Q Richard Lu,Yaqi Deng,Zhaohua Tang,Fanghui Lu","doi":"10.1172/jci195556","DOIUrl":"https://doi.org/10.1172/jci195556","url":null,"abstract":"Glioblastoma (GBM) is a highly lethal brain tumor with limited treatment options and resistance to immune checkpoint inhibitors due to its immunosuppressive tumor microenvironment (TME). Here, we identify OLIG2 as a key regulator of immune evasion in GBM stem-like cells, inhibiting CD8+ T cell-dependent antitumor immunity, while promoting pro-tumor macrophages polarization. Mechanistically, OLIG2 recruits HDAC7 to repress CXCL10 transcription, inducing STAT3 activation in tumor-associated macrophages (TAMs) and decreasing CD8+ T cell infiltration and activation. Genetic deletion of OLIG2 significantly increases CXCL10 secretion, shifting TAMs toward an anti-tumor phenotype and enhancing CD8+ T cell activities. Furthermore, upregulated OLIG2 expression is correlated to resistance to immune checkpoint inhibitors (ICIs) in GBM patients. OLIG2 inhibition by either genetic deficiency or pharmacological targeting with CT-179 sensitizes GBM tumors to anti-PD-L1 therapy, enhancing antitumor immune responses and prolonging survival. Our findings reveal OLIG2+ glioma stem-like cells as critical mediators of immune evasion and identify the OLIG2/HDAC7/CXCL10 axis as a potential therapeutic target to enhance immune checkpoint inhibitors efficacy and to improve immunotherapy outcomes in aggressive GBM.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARP inhibitors (PARPi) may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restore natural killer (NK) cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlates with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells binds to ANXA6 and activates the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocks the FPR1-AKT signaling and diminishes the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolongs survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.
{"title":"PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer.","authors":"Zheng Chao,Le Li,Xiaodong Hao,Hao Peng,Yanan Wang,Chunyu Zhang,Xiangdong Guo,Peikun Liu,Sheng Ma,Junbiao Zhang,Guanyu Qu,Yuzheng Peng,Zhengping Wei,Jing Luo,Bo Liu,Peixiang Lan,Zhihua Wang","doi":"10.1172/jci197157","DOIUrl":"https://doi.org/10.1172/jci197157","url":null,"abstract":"Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARP inhibitors (PARPi) may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restore natural killer (NK) cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlates with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells binds to ANXA6 and activates the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocks the FPR1-AKT signaling and diminishes the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolongs survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Madison L Doolittle,Mitchell N Froemming,Jennifer L Rowsey,Ming Ruan,Leena Sapra,Joshua N Farr,David G Monroe,Sundeep Khosla
Cellular senescence is a heterogeneous phenotype characterized primarily in mesenchymal cells, but the extent to which immune cells differ in their senescence phenotype, or "senotype", is unclear. Here, we applied single-cell approaches alongside both global and cell-specific genetic senolytic mouse models to evaluate the senotype of immune cells in the bone marrow of aging mice. We found that myeloid-lineage cells exhibited the highest expression of p16 and senescence-associated secretory phenotype markers among all immune cell types. In contrast to clearance of p16+ senescent mesenchymal cells, targeted clearance of p16+ myeloid cells in aged mice only had minor effects on age-related bone loss in male mice, with no effects in females. In more detailed analyses, p16+ myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time period. This led to a lack of long-lasting reduction in senescent cell burden, unlike when targeting bone mesenchymal cells. In vitro, myeloid-lineage cells differed markedly from mesenchymal cells in the development of a senescent phenotype. Collectively, our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.
{"title":"Aged murine bone marrow myeloid and mesenchymal cells develop unique senescence phenotypes.","authors":"Madison L Doolittle,Mitchell N Froemming,Jennifer L Rowsey,Ming Ruan,Leena Sapra,Joshua N Farr,David G Monroe,Sundeep Khosla","doi":"10.1172/jci195772","DOIUrl":"https://doi.org/10.1172/jci195772","url":null,"abstract":"Cellular senescence is a heterogeneous phenotype characterized primarily in mesenchymal cells, but the extent to which immune cells differ in their senescence phenotype, or \"senotype\", is unclear. Here, we applied single-cell approaches alongside both global and cell-specific genetic senolytic mouse models to evaluate the senotype of immune cells in the bone marrow of aging mice. We found that myeloid-lineage cells exhibited the highest expression of p16 and senescence-associated secretory phenotype markers among all immune cell types. In contrast to clearance of p16+ senescent mesenchymal cells, targeted clearance of p16+ myeloid cells in aged mice only had minor effects on age-related bone loss in male mice, with no effects in females. In more detailed analyses, p16+ myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time period. This led to a lack of long-lasting reduction in senescent cell burden, unlike when targeting bone mesenchymal cells. In vitro, myeloid-lineage cells differed markedly from mesenchymal cells in the development of a senescent phenotype. Collectively, our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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