Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-11DOI: 10.1016/j.xcrm.2025.101970
Elham Adabi, Filippos T Charitidis, Frederic B Thalheimer, Mar Guaza-Lasheras, Colin Clarke, Christian J Buchholz
{"title":"Enhanced conversion of T cells into CAR T cells by modulation of the MAPK/ERK pathway.","authors":"Elham Adabi, Filippos T Charitidis, Frederic B Thalheimer, Mar Guaza-Lasheras, Colin Clarke, Christian J Buchholz","doi":"10.1016/j.xcrm.2025.101970","DOIUrl":"10.1016/j.xcrm.2025.101970","url":null,"abstract":"<p><p>Delivery of chimeric antigen receptors (CARs) to T cells is usually mediated by lentiviral vectors (LVs), which can have broad tropism or be T cell targeted. To better understand the molecular events during CAR T cell generation, T cell transduction with four different LVs is followed by single-cell multi-omics analysis, distinguishing between transduced T cells and T cells with vector signal but no CAR. We find that only a fraction of the T cells that encounter vectors convert into CAR T cells. Single-cell transcriptome data reveal that interferon-stimulated genes are upregulated in non-transduced cells, whereas extracellular signal-regulated kinase (ERK)2 phosphatases are upregulated in CAR T cells. This expression pattern is evident in CAR T cells from healthy donors and patients. The role of the mitogen-activated protein kinase (MAPK)/ERK pathway in CAR T cell generation is confirmed by chemical inhibitors. These data provide molecular insights into T cell transduction with implications for improving CAR T cell generation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101970"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406013","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}
{"title":"MFGE8 induces anti-PD-1 therapy resistance by promoting extracellular vesicle sorting of PD-L1.","authors":"Wenhui Wang, Jiming Chen, Shibo Wang, Xinhai Sun, Jie Yang, Pengfei Yu, Guinv Hu, Jiang Wang, Jing Zhang, Shuya Qiao, Jianli Wang, Gensheng Zhang, Yuzhou He, Huajun Feng, Zhijian Cai","doi":"10.1016/j.xcrm.2024.101922","DOIUrl":"10.1016/j.xcrm.2024.101922","url":null,"abstract":"<p><p>Anti-PD-1 therapy, effective in patients with various advanced tumors, still encounters the challenge of insensitivity in most patients. Here, we demonstrate that PD-L1 on tumor cell-derived extracellular vesicles (TEVs) is critical for anti-PD-1 therapy resistance. Reducing endogenous and transferring exogenous TEVs abrogates and induces anti-PD-1 therapy resistance, respectively. Notably, PD-L1 is sorted onto TEVs via the endosomal sorting complex required for transport after ubiquitination by UBE4A and gradually upregulated on TEVs with tumor progression. During progression, increased MFGE8 from tumor cells promotes self α<sub>v</sub> integrin signaling activation, enabling themselves to upregulate UBE4A, thereby increasing PD-L1 on TEVs and enhancing their immunosuppressive abilities. Translationally, anti-MFGE8-neutralizing antibodies effectively downregulate UBE4A and TEV PD-L1, thereby negating anti-PD-1 therapy resistance. Furthermore, serum MFGE8 and PD-L1<sup>+</sup> EV levels of tumor patients correlate positively, and high levels of both indicate poor prognosis after anti-PD-1 therapy. Thus, MFGE8 is a promising target for overcoming resistance and predicting responsiveness to anti-PD-1 therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101922"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022284","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}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-01-22DOI: 10.1016/j.xcrm.2024.101924
Hang Zhang, Fan Yang, Ying Xu, Shen Zhao, Yi-Zhou Jiang, Zhi-Ming Shao, Yi Xiao
{"title":"Multimodal integration using a machine learning approach facilitates risk stratification in HR+/HER2- breast cancer.","authors":"Hang Zhang, Fan Yang, Ying Xu, Shen Zhao, Yi-Zhou Jiang, Zhi-Ming Shao, Yi Xiao","doi":"10.1016/j.xcrm.2024.101924","DOIUrl":"10.1016/j.xcrm.2024.101924","url":null,"abstract":"<p><p>Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common type of breast cancer, with continuous recurrence remaining an important clinical issue. Current relapse predictive models in HR+/HER2- breast cancer patients still have limitations. The integration of multidimensional data represents a promising alternative for predicting relapse. In this study, we leverage our multi-omics cohort comprising 579 HR+/HER2- breast cancer patients (200 patients with complete data across 7 modalities) and develop a machine-learning-based model, namely CIMPTGV, which integrates clinical information, immunohistochemistry, metabolomics, pathomics, transcriptomics, genomics, and copy number variations to predict recurrence risk of HR+/HER2- breast cancer. This model achieves concordance indices (C-indices) of 0.871 and 0.869 in the train and test sets, respectively. The risk population predicted by the CIMPTGV model encompasses those identified by single-modality models. Feature analysis reveals that synergistic and complementary effects exist in different modalities. Simultaneously, we develop a simplified model with a mean area under the curve (AUC) of 0.840, presenting a useful approach for clinical applications.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101924"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028059","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}
{"title":"Neoadjuvant immunotherapy with or without chemotherapy in locally advanced oral squamous cell carcinoma: Randomized, two-arm, phase 2 trial.","authors":"Hai-Ming Liu, Xue-Peng Xiong, Zi-Li Yu, Zhe Shao, Gai-Li Chen, Yu-Tong Liu, Xin-Xin Wang, Qiu-Yun Fu, Xiao-Xia Cheng, Jing Li, Jia-Li Zhang, Bo Li, Hong-Yun Gong, Ya-Hua Zhong, Wei Zhang, Jun Jia, Bing Liu, Gang Chen","doi":"10.1016/j.xcrm.2025.101930","DOIUrl":"10.1016/j.xcrm.2025.101930","url":null,"abstract":"<p><p>Patients with locally advanced oral squamous cell carcinoma (OSCC) have poor outcomes with standard care. Neoadjuvant therapy is shown to be effective for these patients. In the randomized, two-arm, phase 2, non-comparative trial, we investigate the efficacy and safety of the neoadjuvant programmed cell death 1 (PD-1) inhibitor camrelizumab with or without docetaxel-cisplatin-5-fluorouracil (TPF) chemotherapy in patients with resectable locally advanced OSCC. Patients with stage III-IVA OSCC receive neoadjuvant therapy with three cycles of camrelizumab (arm Cam) with or without two cycles of TPF chemotherapy (arm Cam+TPF), followed by surgery and adjuvant therapy. Major pathological response (MPR) is achieved in both arm Cam (5/34, 14.7%) and arm Cam+TPF (26/34, 76.4%). With a median follow-up of 32 months, the 2-year event-free survival (EFS) rate of arm Cam and Cam+TPF is 52.9% and 91.2%, respectively. This work demonstrates feasibility and safety for immunochemotherapy in the neoadjuvant setting for OSCC. This study was registered at ClinicalTrials.gov (NCT04649476).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101930"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073939","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}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-05DOI: 10.1016/j.xcrm.2025.101936
Stephanie E Simonds, Jack T Pryor, Brian Y H Lam, Georgina K Dowsett, Tomris Mustafa, Astrid Munder, Kayla Elysee, Eglantine Balland, Lachlan O Cowley, Giles S H Yeo, Andrew Lawrence, David C Spanswick, Michael A Cowley
{"title":"The metabolic and cardiovascular effects of amphetamine are partially mediated by the central melanocortin system.","authors":"Stephanie E Simonds, Jack T Pryor, Brian Y H Lam, Georgina K Dowsett, Tomris Mustafa, Astrid Munder, Kayla Elysee, Eglantine Balland, Lachlan O Cowley, Giles S H Yeo, Andrew Lawrence, David C Spanswick, Michael A Cowley","doi":"10.1016/j.xcrm.2025.101936","DOIUrl":"10.1016/j.xcrm.2025.101936","url":null,"abstract":"<p><p>Amphetamine (AMPH) exerts metabolic and cardiovascular effects. The central melanocortin system is a key regulator of both metabolic and cardiovascular functions. Here, we show that the melanocortin system partially mediates AMPH-induced anorexia, energy expenditure, tachycardia, and hypertension. AMPH increased α-melanocyte stimulating hormone (αMSH) secretion from the hypothalamus, elevated blood pressure and heart rate (HR), increased brown adipose tissue (BAT) thermogenesis, and reduced both food intake (FI) and body weight (BW). In melanocortin 4 receptor-deficient (MC4R knockout [KO]) mice, metabolic and cardiovascular effects of AMPH were significantly attenuated. Antagonism of serotonergic and noradrenergic neurotransmitter systems attenuated AMPH-induced αMSH secretion as well as AMPH-induced metabolic and cardiovascular effects. We propose that AMPH increases serotonergic activation of proopiomelanocortin (POMC) neurons and reduces the noradrenergic inhibition of POMC neurons, thereby disinhibiting them. Together, these presynaptic mechanisms result in increased POMC activity, increased αMSH secretion, and increased activation of MC4R pathways that regulate both the metabolic and cardiovascular systems.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101936"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363771","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}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-10DOI: 10.1016/j.xcrm.2025.101968
Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou
{"title":"Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca<sup>2+</sup> handling across the adult lifespan in men.","authors":"Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou","doi":"10.1016/j.xcrm.2025.101968","DOIUrl":"10.1016/j.xcrm.2025.101968","url":null,"abstract":"<p><p>Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101968"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398479","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}
{"title":"First-in-human phase 1 study of an orally bioavailable vascular-disrupting agent DX1002 in patients with advanced solid tumors.","authors":"Xiao-Li Wei, Hao-Xiang Wu, Dan-Yun Ruan, Feng Wang, Li Xu, Yu-Hong Li, Yu-Xiang Ma, Zhi-Qiang Wang, Yun-Peng Yang, Liang-Wei Tang, Bao-Lin Chen, Zhi-Quan Yong, Rui-Hua Xu, Hong-Yun Zhao","doi":"10.1016/j.xcrm.2025.101969","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101969","url":null,"abstract":"<p><p>DX1002 is an oral vascular-disrupting agent and exhibits promising results in preclinical studies, leading to tumor vasculature destruction and xenografted tumor necrosis in various animal models. In the phase 1 trial, 17 patients with solid tumors receive DX1002 ranging from 50 to 1,100 mg. The maximum tolerated dose and recommended phase 2 dose of DX1002 are determined as 600 mg once daily. The most common treatment-related adverse events are nausea (23.5%), vomiting (17.6%), and fatigue (11.8%). All patients are evaluable for anti-tumor response, 12 of which achieve stable disease as best response. One patient with non-small cell lung cancer achieves a stable disease duration of 6.5 months. The median time to progression (TTP) is 2.70 months (95% confidence interval [CI], 0.90-4.60). Interestingly, reduced blood perfusion is observed by contrast-enhanced ultrasound in a patient with colon cancer. In conclusion, DX1002 is well tolerated and exhibits preliminary anti-tumor efficacy in patients with solid tumors. This study was registered at chictr.org.cn (ChiCTR2400080298).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101969"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457058","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}
{"title":"RSAD2: A pathogenic interferon-stimulated gene at the maternal-fetal interface of patients with systemic lupus erythematosus.","authors":"Xiaoyu Ding, Yonggang Zhou, Xiaofeng Qiu, Xiuxiu Xu, Xinyu Hu, Jingkun Qin, Yulan Chen, Min Zhang, Jieqi Ke, Zhenbang Liu, Ying Zhou, Chen Ding, Nan Shen, Zhigang Tian, Binqing Fu, Haiming Wei","doi":"10.1016/j.xcrm.2025.101974","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101974","url":null,"abstract":"<p><p>Pregnancy disorders in patients with autoimmune diseases or viral infections are often associated with an excessive response of type I interferons. We identify radical S-adenosyl methionine domain containing 2 (RSAD2) as a pathogenic interferon-stimulated gene (ISG) associated with pregnancy complications in systemic lupus erythematosus (SLE). The increased expression of RSAD2 mainly occurs in macrophages and structural cell populations at the maternal-fetal interface of pregnant patients with SLE. The elevation of RSAD2 leads to the accumulation of diacylglycerol lipids in the placenta, impairing the necessary vascular development for the fetus. Depletion of Rsad2 in pregnant mice models exposed to type I interferon inducers significantly reduces lipid accumulation, vascular injury, and embryo development disorders. An RSAD2 inhibitor, L-chicoric acid (LCA), alleviates lipid accumulation and vascular damage, improving pregnancy outcomes in SLE-induced and spontaneous mouse models. This study proposes the potential of targeting RSAD2 to improve pregnancy outcomes in individuals with heightened type I interferon response.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101974"},"PeriodicalIF":11.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472356","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}
{"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":"https://doi.org/10.1016/j.xcrm.2025.101977","url":null,"abstract":"<p><p>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<sup>+</sup> 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.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101977"},"PeriodicalIF":11.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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