Cell Reports Medicine最新文献_第5页

Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 DOI: 10.1016/j.xcrm.2025.102021

Areej Akhtar, Md Shakir, Mohammad Sufyan Ansari, Divya, Md Imam Faizan, Varnit Chauhan, Aashi Singh, Ruquaiya Alam, Iqbal Azmi, Sheetal Sharma, Mehak Pracha, Insha Mohi Uddin, Uzma Bashir, Syeda Najidah Shahni, Rituparna Chaudhuri, Sarah Albogami, Rik Ganguly, Shakti Sagar, Vijay Pal Singh, Gaurav Kharya, Amit Kumar Srivastava, Ulaganathan Mabalirajan, Soumya Sinha Roy, Irfan Rahman, Tanveer Ahmad

{"title":"Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.","authors":"Areej Akhtar, Md Shakir, Mohammad Sufyan Ansari, Divya, Md Imam Faizan, Varnit Chauhan, Aashi Singh, Ruquaiya Alam, Iqbal Azmi, Sheetal Sharma, Mehak Pracha, Insha Mohi Uddin, Uzma Bashir, Syeda Najidah Shahni, Rituparna Chaudhuri, Sarah Albogami, Rik Ganguly, Shakti Sagar, Vijay Pal Singh, Gaurav Kharya, Amit Kumar Srivastava, Ulaganathan Mabalirajan, Soumya Sinha Roy, Irfan Rahman, Tanveer Ahmad","doi":"10.1016/j.xcrm.2025.102021","DOIUrl":"10.1016/j.xcrm.2025.102021","url":null,"abstract":"Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8+ T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102021"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662628","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

Exposure to autoimmune disorders is associated with increased Alzheimer's disease risk in a multi-site electronic health record analysis.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 Epub Date: 2025-02-24 DOI: 10.1016/j.xcrm.2025.101980

Grace D Ramey, Alice Tang, Thanaphong Phongpreecha, Monica M Yang, Sarah R Woldemariam, Tomiko T Oskotsky, Thomas J Montine, Isabel Allen, Zachary A Miller, Nima Aghaeepour, John A Capra, Marina Sirota

{"title":"Exposure to autoimmune disorders is associated with increased Alzheimer's disease risk in a multi-site electronic health record analysis.","authors":"Grace D Ramey, Alice Tang, Thanaphong Phongpreecha, Monica M Yang, Sarah R Woldemariam, Tomiko T Oskotsky, Thomas J Montine, Isabel Allen, Zachary A Miller, Nima Aghaeepour, John A Capra, Marina Sirota","doi":"10.1016/j.xcrm.2025.101980","DOIUrl":"10.1016/j.xcrm.2025.101980","url":null,"abstract":"Autoimmunity has been proposed to increase Alzheimer's disease (AD) risk, but evaluating the clinical connection between autoimmune disorders and AD has been difficult in diverse populations. We investigate risk relationships between 26 autoimmune disorders and AD using retrospective observational case-control and cohort study designs based on electronic health records for >300,000 individuals at the University of California, San Francisco (UCSF) and Stanford University. We discover that autoimmune disorders are associated with increased AD risk (odds ratios [ORs] 1.4-1.7) across study designs, primarily driven by endocrine, gastrointestinal, dermatologic, and musculoskeletal disorders. We also find that autoimmune disorders associate with increased AD risk in both sexes, but the AD sex disparity remains in those with autoimmune disorders: women exhibit higher AD prevalence than men. This study identifies consistent associations between autoimmune disorders and AD across study designs and two real-world clinical databases, establishing a foundation for exploring how autoimmunity may contribute to AD risk.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101980"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499511","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

LTA4H improves the tumor microenvironment and prevents HCC progression via targeting the HNRNPA1/LTBP1/TGF-β axis.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 Epub Date: 2025-03-07 DOI: 10.1016/j.xcrm.2025.102000

Shuai Yang, Xinyao Qiu, Yingcheng Yang, Jing Wu, Shan Wang, Bo Zheng, Jianmin Wu, Tao Zhou, Yangqianwen Zhang, Mixue Bai, Shuowu Liu, Zihan Zhao, Yani Zhang, Yixian Wang, Jinxia Bao, Mengye Wu, Dongdong Xue, Meiyu Bao, Ji Hu, Siyun Shen, Hongyang Wang, Lei Chen

{"title":"LTA4H improves the tumor microenvironment and prevents HCC progression via targeting the HNRNPA1/LTBP1/TGF-β axis.","authors":"Shuai Yang, Xinyao Qiu, Yingcheng Yang, Jing Wu, Shan Wang, Bo Zheng, Jianmin Wu, Tao Zhou, Yangqianwen Zhang, Mixue Bai, Shuowu Liu, Zihan Zhao, Yani Zhang, Yixian Wang, Jinxia Bao, Mengye Wu, Dongdong Xue, Meiyu Bao, Ji Hu, Siyun Shen, Hongyang Wang, Lei Chen","doi":"10.1016/j.xcrm.2025.102000","DOIUrl":"10.1016/j.xcrm.2025.102000","url":null,"abstract":"Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206+ macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102000"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582219","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

CD4⁺ anti-TGF-β CAR T cells and CD8⁺ conventional CAR T cells exhibit synergistic antitumor effects.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 DOI: 10.1016/j.xcrm.2025.102020

Diwei Zheng, Le Qin, Jiang Lv, Meihui Che, Bingjia He, Yongfang Zheng, Shouheng Lin, Yuekun Qi, Ming Li, Zhaoyang Tang, Bin-Chao Wang, Yi-Long Wu, Robert Weinkove, Georgia Carson, Yao Yao, Nathalie Wong, James Lau, Jean Paul Thiery, Dajiang Qin, Bin Pan, Kailin Xu, Zhenfeng Zhang, Peng Li

{"title":"CD4+ anti-TGF-β CAR T cells and CD8+ conventional CAR T cells exhibit synergistic antitumor effects.","authors":"Diwei Zheng, Le Qin, Jiang Lv, Meihui Che, Bingjia He, Yongfang Zheng, Shouheng Lin, Yuekun Qi, Ming Li, Zhaoyang Tang, Bin-Chao Wang, Yi-Long Wu, Robert Weinkove, Georgia Carson, Yao Yao, Nathalie Wong, James Lau, Jean Paul Thiery, Dajiang Qin, Bin Pan, Kailin Xu, Zhenfeng Zhang, Peng Li","doi":"10.1016/j.xcrm.2025.102020","DOIUrl":"10.1016/j.xcrm.2025.102020","url":null,"abstract":"Transforming growth factor (TGF)-β1 restricts the expansion, survival, and function of CD4+ T cells. Here, we demonstrate that CD4+ but not CD8+ anti-TGF-β CAR T cells (T28zT2 T cells) can suppress tumor growth partly through secreting Granzyme B and interferon (IFN)-γ. TGF-β1-treated CD4+ T28zT2 T cells persist well in peripheral blood and tumors, maintain their mitochondrial form and function, and do not cause in vivo toxicity. They also improve the expansion and persistence of untransduced CD8+ T cells in vivo. Tumor-infiltrating CD4+ T28zT2 T cells are enriched with TCF-1+IL7R+ memory-like T cells, express NKG2D, and downregulate T cell exhaustion markers, including PD-1 and LAG3. Importantly, a combination of CD4+ T28zT2 T cells and CD8+ anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells exhibits augmented antitumor effects in xenografts. These findings suggest that rewiring TGF-β signaling with T28zT2 in CD4+ T cells is a promising strategy for eradicating solid tumors.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102020"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662629","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

Safety and efficacy of combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus TILT-123 in metastatic melanoma.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 DOI: 10.1016/j.xcrm.2025.102016

Tine J Monberg, Santeri A Pakola, Benedetta Albieri, Eva Ellebaek, Marco Donia, Rikke L Eefsen, Troels H Borch, Tatiana V Kudling, Torben Lorentzen, Helle W Hendel, Cecilie Vestergaard, Cathrine Lorentzen, Rikke B Holmstroem, Victor Arias, Amir Khammari, Claudia Kistler, João M Santos, James H A Clubb, Lyna Haybout, Marie C W Westergaard, Özcan Met, Dafne C A Quixabeira, Elise Jirovec, Riikka Havunen, Suvi Sorsa, Victor Cervera-Carrascon, Brigitte Dreno, Akseli Hemminki, Inge Marie Svane

{"title":"Safety and efficacy of combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus TILT-123 in metastatic melanoma.","authors":"Tine J Monberg, Santeri A Pakola, Benedetta Albieri, Eva Ellebaek, Marco Donia, Rikke L Eefsen, Troels H Borch, Tatiana V Kudling, Torben Lorentzen, Helle W Hendel, Cecilie Vestergaard, Cathrine Lorentzen, Rikke B Holmstroem, Victor Arias, Amir Khammari, Claudia Kistler, João M Santos, James H A Clubb, Lyna Haybout, Marie C W Westergaard, Özcan Met, Dafne C A Quixabeira, Elise Jirovec, Riikka Havunen, Suvi Sorsa, Victor Cervera-Carrascon, Brigitte Dreno, Akseli Hemminki, Inge Marie Svane","doi":"10.1016/j.xcrm.2025.102016","DOIUrl":"10.1016/j.xcrm.2025.102016","url":null,"abstract":"Tumor-infiltrating lymphocytes (TILs) are effective in the treatment of metastatic melanoma (MM), but toxicity limits its application. TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus producing interleukin-2 (IL-2) and tumor necrosis factor (TNF) upon replication. In this phase 1 trial, 17 patients with metastatic checkpoint inhibitor-resistant melanoma are treated with TILT-123 and TILs without preconditioning chemotherapy or postconditioning IL-2. The treatment is safe and feasible. According to computed tomography (CT), the objective response rate is 11.7% (2/17) and disease control is observed in 35% (6/17), including a partial response lasting >8 months and a durable complete response in a mucosal melanoma patient. According to positron emission tomography (PET), disease control is observed in 7/15 (47%) with minor or partial responses in 4/15 (27%). In the initial TILT-123 monotherapy phase of the trial, disease control is observed in 6/17 (35%) and 10/16 (63%) in CT and PET, respectively. The study demonstrates good tolerability and preliminary efficacy.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102016"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662636","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 IFN-high phenotype: A biomarker-driven breakthrough in colorectal cancer treatment.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 DOI: 10.1016/j.xcrm.2025.102025

Lize Allonsius, Luca Kelecom, Damya Laoui

引用次数: 0

Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 Epub Date: 2025-02-20 DOI: 10.1016/j.xcrm.2025.101977

Haoran Mu, Qi Zhang, Dongqing Zuo, Jinzeng Wang, Yining Tao, Zhen Li, Xin He, Huanliang Meng, Hongsheng Wang, Jiakang Shen, Mengxiong Sun, Yafei Jiang, Weisong Zhao, Jing Han, Mengkai Yang, Zhuoying Wang, Yu Lv, Yuqin Yang, Jing Xu, Tao Zhang, Liu Yang, Jun Lin, Feng Tang, Renhong Tang, Haiyan Hu, Zhengdong Cai, Wei Sun, Yingqi Hua

{"title":"Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma.","authors":"Haoran Mu, Qi Zhang, Dongqing Zuo, Jinzeng Wang, Yining Tao, Zhen Li, Xin He, Huanliang Meng, Hongsheng Wang, Jiakang Shen, Mengxiong Sun, Yafei Jiang, Weisong Zhao, Jing Han, Mengkai Yang, Zhuoying Wang, Yu Lv, Yuqin Yang, Jing Xu, Tao Zhang, Liu Yang, Jun Lin, Feng Tang, Renhong Tang, Haiyan Hu, Zhengdong Cai, Wei Sun, Yingqi Hua","doi":"10.1016/j.xcrm.2025.101977","DOIUrl":"10.1016/j.xcrm.2025.101977","url":null,"abstract":"Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we identify a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a \"cold\" tumor microenvironment. MTAP-deleted OS relies on methionine metabolism and is sensitive to methionine intervention, achieved through either dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We further demonstrate that methionine intervention triggers programmed death-ligand 1 (PD-L1) transcription factor IKAROS family zinc finger 1 (IKZF1) and enhances PD-L1 expression in MTAP-deleted OS cells. Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8+ T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101977"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472354","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

High-dimensional analysis of injured patients reveals distinct circulating proteomic profiles in plasma vs. whole blood resuscitation.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 DOI: 10.1016/j.xcrm.2025.102022

Hamed Moheimani, Xuejing Sun, Mehves Ozel, Jennifer L Darby, Erika P Ong, Tunde Oyebamiji, Upendra K Kar, Mark H Yazer, Matthew D Neal, Francis X Guyette, Stephen R Wisniewski, Bryan A Cotton, Jeremy W Cannon, Martin A Schreiber, Ernest E Moore, Nicholas Namias, Joseph P Minei, Christopher D Barrett, Jishnu Das, Jason L Sperry, Timothy R Billiar

{"title":"High-dimensional analysis of injured patients reveals distinct circulating proteomic profiles in plasma vs. whole blood resuscitation.","authors":"Hamed Moheimani, Xuejing Sun, Mehves Ozel, Jennifer L Darby, Erika P Ong, Tunde Oyebamiji, Upendra K Kar, Mark H Yazer, Matthew D Neal, Francis X Guyette, Stephen R Wisniewski, Bryan A Cotton, Jeremy W Cannon, Martin A Schreiber, Ernest E Moore, Nicholas Namias, Joseph P Minei, Christopher D Barrett, Jishnu Das, Jason L Sperry, Timothy R Billiar","doi":"10.1016/j.xcrm.2025.102022","DOIUrl":"10.1016/j.xcrm.2025.102022","url":null,"abstract":"Early blood product resuscitation is often essential for optimal trauma care. However, the effects of different products on the underlying trauma-induced coagulopathy and immune dysfunction are not well described. Here, we use high-dimensional analysis and causal modeling in a longitudinal study to explore the circulating proteomic response to plasma as a distinct component versus low-titer O whole blood (LTOWB), which contains plasma. We highlight the differential impacts of plasma and LTOWB on immune mediator levels and the distinct capacity of plasma to modulate coagulation by elevating fibrinogen and factor XIII and reducing platelet factor 4. A higher proportion of plasma in prehospital resuscitation is associated with improved admission time coagulation parameters in patients with severe shock and elevated brain injury markers and reduced post-admission transfusion volumes in those suffering from traumatic brain injury (TBI) and blunt injury. While LTOWB offers broad hemostatic benefits, our findings demonstrate specific advantages of plasma and support individualized transfusion strategies.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102022"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662630","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

ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma. ACVR2A 的衰减会影响肝细胞癌中吸引调节性 T 细胞的乳酸生成和高糖化条件。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 DOI: 10.1016/j.xcrm.2025.102038

Koya Yasukawa, Shu Shimada, Yoshimitsu Akiyama, Tomohiko Taniai, Yosuke Igarashi, Shu Tsukihara, Yoshiaki Tanji, Kentaro Umemura, Atsushi Kamachi, Atsushi Nara, Masahiro Yamane, Keiichi Akahoshi, Akira Shimizu, Yuji Soejima, Minoru Tanabe, Shinji Tanaka

{"title":"ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma.","authors":"Koya Yasukawa, Shu Shimada, Yoshimitsu Akiyama, Tomohiko Taniai, Yosuke Igarashi, Shu Tsukihara, Yoshiaki Tanji, Kentaro Umemura, Atsushi Kamachi, Atsushi Nara, Masahiro Yamane, Keiichi Akahoshi, Akira Shimizu, Yuji Soejima, Minoru Tanabe, Shinji Tanaka","doi":"10.1016/j.xcrm.2025.102038","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102038","url":null,"abstract":"Although ACVR2A mutations are prevalent in non-viral hepatocellular carcinomas (HCCs), the underlying mechanism remains unelucidated. Our molecular investigation reveals that ACVR2A impairment induces hyperglycolysis through the inactivation of the SMAD signaling pathway. Using syngeneic transplantation models and human clinical samples, we clarify that ACVR2A-deficient HCC cells produce and secrete lactate via the upregulation of lactate dehydrogenase A (LDHA) and monocarboxylate transporter 4 (MCT4) expression levels, which promotes regulatory T (Treg) cell accumulation and then acquires resistance to immune checkpoint inhibitors. Remarkably, genetic knockdown and pharmacological inhibition of MCT4 ameliorate the high-lactate milieu in ACVR2A-deficient HCC, resulting in the suppression of intratumoral Treg cell recruitment and the restoration of the sensitivity to PD-1 blockade. These findings furnish compelling evidence that lactate attenuates anti-tumor immunity and that therapeutics targeting this pathway present a promising strategy for mitigating immunotherapy resistance in ACVR2A-deficient HCC.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102038"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728722","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

A strain-transcending anti-AMA1 human monoclonal antibody neutralizes malaria parasites independent of direct RON2L receptor blockade.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-03-18 Epub Date: 2025-02-27 DOI: 10.1016/j.xcrm.2025.101985

Palak N Patel, Ababacar Diouf, Thayne H Dickey, Wai Kwan Tang, Christine S Hopp, Boubacar Traore, Carole A Long, Kazutoyo Miura, Peter D Crompton, Niraj H Tolia

{"title":"A strain-transcending anti-AMA1 human monoclonal antibody neutralizes malaria parasites independent of direct RON2L receptor blockade.","authors":"Palak N Patel, Ababacar Diouf, Thayne H Dickey, Wai Kwan Tang, Christine S Hopp, Boubacar Traore, Carole A Long, Kazutoyo Miura, Peter D Crompton, Niraj H Tolia","doi":"10.1016/j.xcrm.2025.101985","DOIUrl":"10.1016/j.xcrm.2025.101985","url":null,"abstract":"Plasmodium falciparum apical membrane antigen 1 (AMA1) binds a loop in rhoptry neck protein 2 (RON2L) during red cell invasion and is a target for vaccines and therapeutic antibodies against malaria. Here, we report a panel of AMA1-specific naturally acquired human monoclonal antibodies (hmAbs) derived from individuals living in malaria-endemic regions. Two neutralizing hmAbs engage AMA1 independent of the RON2L-binding site. The hmAb 75B10 demonstrates potent strain-transcending neutralization that is independent of RON2L blockade, emphasizing that epitopes outside the RON2L-binding site elicit broad protection against variant parasite strains. The combination of these hmAbs synergistically enhances parasite neutralization. Vaccination with a structure-based design (SBD1) that mimics the AMA1-RON2L complex elicited antibodies similar to the two neutralizing hmAbs connecting vaccination to naturally acquired immunity in humans. The structural definition of a strain-transcending epitope on AMA1 targeted by naturally acquired hmAb establishes paradigms for developing AMA1-based vaccines and therapeutic antibodies.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101985"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531347","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