Journal of Clinical Investigation最新文献

An inducible RIPK3-driven necroptotic system enhances cancer cell-based immunotherapy and ensures safety. 可诱导的 RIPK3 驱动坏死系统可增强基于癌细胞的免疫疗法并确保其安全性。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-19 DOI: 10.1172/JCI181143

Kok-Siong Chen, Sarah Manoury-Battais, Nobuhiko Kanaya, Ioulia Vogiatzi, Paulo Borges, Sterre J Kruize, Yi-Ching Chen, Laura Y Lin, Filippo Rossignoli, Natalia Claire Mendonca, Khalid Shah

{"title":"An inducible RIPK3-driven necroptotic system enhances cancer cell-based immunotherapy and ensures safety.","authors":"Kok-Siong Chen, Sarah Manoury-Battais, Nobuhiko Kanaya, Ioulia Vogiatzi, Paulo Borges, Sterre J Kruize, Yi-Ching Chen, Laura Y Lin, Filippo Rossignoli, Natalia Claire Mendonca, Khalid Shah","doi":"10.1172/JCI181143","DOIUrl":"10.1172/JCI181143","url":null,"abstract":"Recent progress in cancer cell-based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible RIPK3-driven necroptotic system that serves as a dual function of safety switch as well as inducing immunogenic cell death which in turn stimulates antitumor immune responses. We showed that activating RIPK3 safety switch triggered immunogenic responses marked by an increased release of adenosine triphosphate (ATP) and damage-associated molecular patterns (DAMPs). Compared to other existing safety switches, incorporating RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, RIPK3 system reinvigorated the TIME by promoting dendritic cell (DC) maturation, polarizing the macrophages towards the M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell-based therapy, with broader implications for cellular therapies.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667905","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

Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice. 小鼠体内三肽链蛋白的低表达激活了表型可塑性，并为向致命性前列腺癌的过渡奠定了基础。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-19 DOI: 10.1172/JCI175680

Katherine L Morel, Beatriz Germán, Anis A Hamid, Jagpreet S Nanda, Simon Linder, Andries M Bergman, Henk van der Poel, Ingrid Hofland, Elise M Bekers, Shana Y Trostel, Deborah L Burkhart, Scott Wilkinson, Anson T Ku, Minhyung Kim, Jina Kim, Duanduan Ma, Jasmine T Plummer, Sungyong You, Xiaofeng A Su, Wilbert Zwart, Adam G Sowalsky, Christopher J Sweeney, Leigh Ellis

{"title":"Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice.","authors":"Katherine L Morel, Beatriz Germán, Anis A Hamid, Jagpreet S Nanda, Simon Linder, Andries M Bergman, Henk van der Poel, Ingrid Hofland, Elise M Bekers, Shana Y Trostel, Deborah L Burkhart, Scott Wilkinson, Anson T Ku, Minhyung Kim, Jina Kim, Duanduan Ma, Jasmine T Plummer, Sungyong You, Xiaofeng A Su, Wilbert Zwart, Adam G Sowalsky, Christopher J Sweeney, Leigh Ellis","doi":"10.1172/JCI175680","DOIUrl":"10.1172/JCI175680","url":null,"abstract":"Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance to androgen receptor (AR)-targeted therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it's critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP, gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo, induced prostatic intraepithelial neoplasia, and, with Pten co-deletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, demonstrated by enrichment of EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor, dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667917","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

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition. 肿瘤细胞衍生的亚精胺通过抑制 CD8+ T 细胞促进胶质母细胞瘤的促肿瘤免疫微环境。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-19 DOI: 10.1172/JCI177824

Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily R Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin Lathia

{"title":"Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.","authors":"Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily R Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin Lathia","doi":"10.1172/JCI177824","DOIUrl":"10.1172/JCI177824","url":null,"abstract":"The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667926","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

G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates. ELANE突变型中性粒细胞减少症的G-CSF抗性取决于含有截短的中性粒细胞弹性蛋白酶聚集体的SERF1。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-19 DOI: 10.1172/JCI177342

Ramesh C Nayak, Sana Emberesh, Lisa Trump, Ashley Wellendorf, Abhishek Singh, Brice Korkmaz, Marshall S Horwitz, Kasiani C Myers, Theodosia A Kalfa, Carolyn Lutzko, Jose A Cancelas

{"title":"G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates.","authors":"Ramesh C Nayak, Sana Emberesh, Lisa Trump, Ashley Wellendorf, Abhishek Singh, Brice Korkmaz, Marshall S Horwitz, Kasiani C Myers, Theodosia A Kalfa, Carolyn Lutzko, Jose A Cancelas","doi":"10.1172/JCI177342","DOIUrl":"10.1172/JCI177342","url":null,"abstract":"Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667912","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

Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation. 乳酸通过CBX3调控的组蛋白乳酰化重编程胶质母细胞瘤免疫。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI176851

Shuai Wang, Tengfei Huang, Qiulian Wu, Huairui Yuan, Xujia Wu, Fanen Yuan, Tingting Duan, Suchet Taori, Yingming Zhao, Nathaniel W Snyder, Dimitris G Placantonakis, Jeremy N Rich

{"title":"Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation.","authors":"Shuai Wang, Tengfei Huang, Qiulian Wu, Huairui Yuan, Xujia Wu, Fanen Yuan, Tingting Duan, Suchet Taori, Yingming Zhao, Nathaniel W Snyder, Dimitris G Placantonakis, Jeremy N Rich","doi":"10.1172/JCI176851","DOIUrl":"10.1172/JCI176851","url":null,"abstract":"Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a \"don't eat me\" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638922","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

Rg3-lipo biomimetic delivery of paclitaxel enhances targeting of tumors and myeloid-derived suppressor cells. Rg3-lipo 紫杉醇生物仿生递送增强了对肿瘤和髓源性抑制细胞的靶向性。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI178617

Yuru Shen, Bin Zhong, Wanwei Zheng, Dan Wang, Lin Chen, Huan Song, Xuanxuan Pan, Shaocong Mo, Bryan Jin, Haoshu Cui, Huaxing Zhan, Feifei Luo, Jie Liu

{"title":"Rg3-lipo biomimetic delivery of paclitaxel enhances targeting of tumors and myeloid-derived suppressor cells.","authors":"Yuru Shen, Bin Zhong, Wanwei Zheng, Dan Wang, Lin Chen, Huan Song, Xuanxuan Pan, Shaocong Mo, Bryan Jin, Haoshu Cui, Huaxing Zhan, Feifei Luo, Jie Liu","doi":"10.1172/JCI178617","DOIUrl":"10.1172/JCI178617","url":null,"abstract":"Liposomal drug delivery systems have revolutionized traditional cytotoxic drugs. However, the relative instability and toxicity of the existing liposomal drug delivery systems compromised their efficacy. Herein, we present Rg3-lipo, an innovative drug delivery system using a glycosyl moiety-enriched ginsenoside (Rg3). This system is distinguished by its glycosyl moieties exposed on the liposomal surface. These moieties imitate human cell membranes to stabilize and evade phagocytic clearance. The Rg3-lipo system loaded with paclitaxel (PTX-Rg3-lipo) demonstrated favorable bioavailability and safety in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys. With its glycosyl moieties recognizing tumor cells via the glucose transporter Glut1, PTX-Rg3-lipo inhibited gastric, breast, and esophageal cancers in human cancer cell lines, tumor-bearing mice, and patient-derived xenograft models. These glycosyl moieties selectively targeted myeloid-derived suppressor cells (MDSCs) through the glucose transporter Glut3 to attenuate their immunosuppressive effect. The mechanism study revealed that Rg3-lipo suppressed glycolysis and downregulated the transcription factors c-Maf and Mafb overcoming the MDSC-mediated immunosuppressive microenvironment and enhancing PTX-Rg3-lipo's antitumor effect. Taken together, we supply substantial evidence for its advantageous bioavailability and safety in multiple animal models, including nonhuman primates, and Rg3-lipo's dual targeting of cancer cells and MDSCs. Further investigation regarding Rg3-lipo's druggability will be conducted in clinical trials.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638943","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

Transparency, bias, and reproducibility across science: a meta-research view. 科学的透明度、偏见和可重复性：元研究视角。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI181923

John Pa Ioannidis

引用次数: 0

Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy. 胰岛素样生长因子2驱动成纤维细胞介导的肿瘤免疫侵袭，并赋予免疫疗法抗药性。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI183366

Daqiang Song, Yushen Wu, Jie Li, Jiazhou Liu, Ziying Yi, Xiaoyu Wang, Jiazheng Sun, Liuying Li, Qianxue Wu, Yuru Chen, Huiying Fang, Tiankuo Luan, Huimin Du, Jing Huang, Weiyan Peng, Yuxian Wei, Fan Li, Qin Li, Li Zhang, Yong Zhu, Jingyuan Wan, Guosheng Ren, Hongzhong Li

{"title":"Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy.","authors":"Daqiang Song, Yushen Wu, Jie Li, Jiazhou Liu, Ziying Yi, Xiaoyu Wang, Jiazheng Sun, Liuying Li, Qianxue Wu, Yuru Chen, Huiying Fang, Tiankuo Luan, Huimin Du, Jing Huang, Weiyan Peng, Yuxian Wei, Fan Li, Qin Li, Li Zhang, Yong Zhu, Jingyuan Wan, Guosheng Ren, Hongzhong Li","doi":"10.1172/JCI183366","DOIUrl":"10.1172/JCI183366","url":null,"abstract":"T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti-programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638915","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

Nuclear PD-L1 compartmentalization suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance in mice via histone macroH2A1. 核PD-L1分区通过组蛋白宏H2A1抑制小鼠的肿瘤发生并克服免疫检查点疗法的耐药性。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI181314

Yong Liu, Zhi Yang, Shuanglian Wang, Rui Miao, Chiung-Wen Mary Chang, Jingyu Zhang, Xin Zhang, Mien-Chie Hung, Junwei Hou

{"title":"Nuclear PD-L1 compartmentalization suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance in mice via histone macroH2A1.","authors":"Yong Liu, Zhi Yang, Shuanglian Wang, Rui Miao, Chiung-Wen Mary Chang, Jingyu Zhang, Xin Zhang, Mien-Chie Hung, Junwei Hou","doi":"10.1172/JCI181314","DOIUrl":"10.1172/JCI181314","url":null,"abstract":"Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies have observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more markedly in immunocompetent mice. Phosphorylated AMPKα (p-AMPKα) facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK/STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which likely resulted from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to interferon-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638930","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

The lung is a megakaryocyte outpost that can defend against thrombocytopenic attack. 肺是巨核细胞的前哨，可以抵御血小板减少症的侵袭。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI186111

Anthony K Yeung, George J Murphy

引用次数: 0