Translational Research最新文献

{"title":"Information for Readers","authors":"","doi":"10.1016/S1931-5244(24)00128-2","DOIUrl":"https://doi.org/10.1016/S1931-5244(24)00128-2","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"270 ","pages":"Page IBC"},"PeriodicalIF":7.8,"publicationDate":"2024-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141302850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIR8 protects against nonalcoholic steatohepatitis by antagonizing lipotoxicity-induced PPARα downregulation and reducing the sensitivity of hepatocytes to LPS","authors":"Xu Shi ,&nbsp;Wenyan Jiang ,&nbsp;Xiaoguang Yang ,&nbsp;Yanan Li ,&nbsp;Xiaodan Zhong ,&nbsp;Junqi Niu ,&nbsp;Ying Shi","doi":"10.1016/j.trsl.2024.06.002","DOIUrl":"10.1016/j.trsl.2024.06.002","url":null,"abstract":"<div><p>In up to one-third of nonalcoholic fatty liver disease (NAFLD) patients, simple steatosis progresses to its more severe form, nonalcoholic steatohepatitis (NASH), but the precise mechanisms underlying this transition are not fully understood. Toll/interleukin-1 receptor 8 (TIR8), a conventional innate immune regulator highly expressed in hepatic tissue, has shown potential for ameliorating various inflammation-related disorders. However, its role in NASH pathogenesis, especially its regulatory effects on lipid metabolism and inflammatory responses, is still unclear. Here, using a TIR8 knockout (TIR8KO) mouse model and mass spectrometry analyses, we found that TIR8KO mice displayed aggravated hepatic steatosis and inflammation, whereas TIR8 overexpression attenuated these adverse effects. Ectopic TIR8 expression counteracts free fatty acid (FFA)-induced PPARα inhibition and downstream signaling. A decrease in TIR8 levels in hepatocytes heightened lipopolysaccharide (LPS) sensitivity. Notably, FFA stimulation led to a direct interaction between TIR8 and proteasome subunit alpha type 4 (PSMA4), facilitating TIR8 degradation. These results revealed that TIR8 safeguards PPARα-regulated lipid metabolism and mitigates inflammation induced by external factors during NASH progression. Our study highlights TIR8 as a promising target for NASH therapy, indicating the potential of TIR8 agonists in treatment strategies.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"272 ","pages":"Pages 68-80"},"PeriodicalIF":7.8,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141294063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA MFRL regulates the phenotypic switch of vascular smooth muscle cells to attenuate arterial remodeling by encoding a novel micropeptide MFRLP","authors":"Xiaocong Liu ,&nbsp;Siyu Chen ,&nbsp;Wei Luo ,&nbsp;Chen Yu ,&nbsp;Shaohua Yan ,&nbsp;Li Lei ,&nbsp;Shifeng Qiu ,&nbsp;Xinxin Lin ,&nbsp;Ting Feng ,&nbsp;Jinglin Shi ,&nbsp;Qiuxia Zhang ,&nbsp;Hongbin Liang ,&nbsp;Xuewei Liu ,&nbsp;Alex Pui-Wai Lee ,&nbsp;Lei Zheng ,&nbsp;Xinlu Zhang ,&nbsp;Jiancheng Xiu","doi":"10.1016/j.trsl.2024.05.009","DOIUrl":"10.1016/j.trsl.2024.05.009","url":null,"abstract":"<div><h3>Background</h3><p>Arterial remodeling is a common pathophysiological change in the pathogenesis of cardiovascular diseases in which the phenotypic switch of vascular smooth muscle cells (VSMC) plays an important role. Recently, an increasing number of long non-coding RNAs(lncRNAs) have been shown to encode micropeptides that play biological roles and have great clinical transformation potential. However, the role of micropeptides encoded by lncRNAs in arterial remodeling has not been well studied and requires further exploration.</p></div><div><h3>Methods and Results</h3><p>Through bioinformatic analysis and experimental verification, we found that a new lncRNA, the mitochondrial function-related lncRNA (<em>MFRL</em>), encodes a 64-amino acid micropeptide, MFRLP. <em>MFRL</em> and MFRLP play important roles in the phenotypic switch of VSMC. Further experiments showed that MFRLP interacts with mitochondrial cytochrome b to reduce accumulation of reactive oxygen species, suppress mitophagy and inhibit the VSMC switch from contractile to synthetic phenotype.</p></div><div><h3>Conclusions</h3><p>LncRNA <em>MFRL</em> encodes the micropeptide MFRLP, which interacts with mitochondrial cytochrome b to inhibit the VSMC switch from contractile to synthetic phenotype and improve arterial remodeling.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"272 ","pages":"Pages 54-67"},"PeriodicalIF":7.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141262225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking the future of cancer diagnosis – promises and challenges of ctDNA-based liquid biopsies in non-small cell lung cancer","authors":"Chiara Reina ,&nbsp;Berina Šabanović ,&nbsp;Chiara Lazzari ,&nbsp;Vanesa Gregorc ,&nbsp;Christopher Heeschen","doi":"10.1016/j.trsl.2024.05.014","DOIUrl":"10.1016/j.trsl.2024.05.014","url":null,"abstract":"<div><p>The advent of liquid biopsies has brought significant changes to the diagnosis and monitoring of non-small cell lung cancer (NSCLC), presenting both promise and challenges. Molecularly targeted drugs, capable of enhancing survival rates, are now available to around a quarter of NSCLC patients. However, to ensure their effectiveness, precision diagnosis is essential. Circulating tumor DNA (ctDNA) analysis as the most advanced liquid biopsy modality to date offers a non-invasive method for tracking genomic changes in NSCLC.</p><p>The potential of ctDNA is particularly rooted in its ability to furnish comprehensive (epi-)genetic insights into the tumor, thereby aiding personalized treatment strategies. One of the key advantages of ctDNA-based liquid biopsies in NSCLC is their ability to capture tumor heterogeneity. This capability ensures a more precise depiction of the tumor's (epi-)genomic landscape compared to conventional tissue biopsies. Consequently, it facilitates the identification of (epi-)genetic alterations, enabling informed treatment decisions, disease progression monitoring, and early detection of resistance-causing mutations for timely therapeutic interventions.</p><p>Here we review the current state-of-the-art in ctDNA-based liquid biopsy technologies for NSCLC, exploring their potential to revolutionize clinical practice. Key advancements in ctDNA detection methods, including PCR-based assays, next-generation sequencing (NGS), and digital PCR (dPCR), are discussed, along with their respective strengths and limitations. Additionally, the clinical utility of ctDNA analysis in guiding treatment decisions, monitoring treatment response, detecting minimal residual disease, and identifying emerging resistance mechanisms is examined. Liquid biopsy analysis bears the potential of transforming NSCLC management by enabling non-invasive monitoring of Minimal Residual Disease and providing early indicators for response to targeted treatments including immunotherapy. Furthermore, considerations regarding sample collection, processing, and data interpretation are highlighted as crucial factors influencing the reliability and reproducibility of ctDNA-based assays. Addressing these challenges will be essential for the widespread adoption of ctDNA-based liquid biopsies in routine clinical practice, ultimately paving the way toward personalized medicine and improved outcomes for patients with NSCLC.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"272 ","pages":"Pages 41-53"},"PeriodicalIF":7.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141262243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DC-derived CXCL10 promotes CTL activation to suppress ovarian cancer","authors":"Ming Dong ,&nbsp;Lili Lu ,&nbsp;Hui Xu ,&nbsp;Zhengyi Ruan","doi":"10.1016/j.trsl.2024.05.013","DOIUrl":"10.1016/j.trsl.2024.05.013","url":null,"abstract":"<div><p>This study investigates the role of dendritic cells (DCs), with a focus on their CXCL10 marker gene, in the activation of cytotoxic T lymphocytes (CTLs) within the ovarian cancer microenvironment and its impact on disease progression. Utilizing scRNA-seq data and immune infiltration analysis, we identified a diminished DC presence in ovarian cancer. Gene analysis pinpointed CXCL10 as a key regulator in OV progression via its influence on DCs and CTLs. Prognostic analysis and in vitro experiments substantiated this role. Our findings reveal that DC-derived CXCL10 significantly affects CTL activation and proliferation. Reduced CXCL10 levels hinder CTL cytotoxicity, promoting ovarian cancer cell migration and invasion. Experimental studies using animal models have provided further evidence that the capacity of CTLs to suppress tumor development is significantly diminished when treated with DCs that have low expression of CXCL10. Dendritic cell-derived CXCL10 emerges as a pivotal factor in restraining ovarian cancer growth and metastasis through the activation of cytotoxic T lymphocytes. This study sheds light on the crucial interplay within the ovarian cancer microenvironment, offering potential therapeutic targets for ovarian cancer treatment.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"272 ","pages":"Pages 126-139"},"PeriodicalIF":6.4,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141187238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing reveals the MIF/ACKR3 receptor-ligand interaction between neutrophils and nucleus pulposus cells in intervertebral disc degeneration","authors":"Tao-Lan Zhang ,&nbsp;Wen-Kang Chen ,&nbsp;Xian-Peng Huang ,&nbsp;Bo-Wen Zheng ,&nbsp;Peng-Fei Wu ,&nbsp;Bo-Yv Zheng ,&nbsp;Ling-Xiang Jiang ,&nbsp;David Escobar ,&nbsp;Jing Li ,&nbsp;Guo-Hua Lv ,&nbsp;Wei Huang ,&nbsp;Hong Zhou ,&nbsp;Zhun Xu ,&nbsp;Ming-Xiang Zou","doi":"10.1016/j.trsl.2024.05.011","DOIUrl":"10.1016/j.trsl.2024.05.011","url":null,"abstract":"<div><h3>Objectives</h3><p>To unravel the heterogeneity and function of microenvironmental neutrophils during intervertebral disc degeneration (IDD).</p></div><div><h3>Methods</h3><p>Single-cell RNA sequencing (scRNA-seq) was utilized to dissect the cellular landscape of neutrophils in intervertebral disc (IVD) tissues and their crosstalk with nucleus pulposus cells (NPCs). The expression levels of macrophage migration inhibitory factor (MIF) and ACKR3 in IVD tissues were detected. The MIF/ACKR3 axis was identified and its effects on IDD were investigated <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Results</h3><p>We sequenced here 71520 single cells from 5 control and 9 degenerated IVD samples using scRNA-seq. We identified a unique cluster of neutrophils abundant in degenerated IVD tissues that highly expressed MIF and was functionally enriched in extracellular matrix organization (ECMO). Cell-to-cell communication analyses showed that this ECMO-neutrophil subpopulation was closely interacted with an effector NPCs subtype, which displayed high expression of ACKR3. Further analyses revealed that MIF was positively correlated with ACKR3 and functioned via directly binding to ACKR3 on effector NPCs. MIF inhibition attenuated degenerative changes of NPCs and extracellular matrix, which could be partially reversed by ACKR3 overexpression. Clinically, a significant correlation of high MIF/ACKR3 expression with advanced IDD grade was observed. Furthermore, we also found a positive association between MIF⁺ ECMO-neutrophil counts and ACKR3⁺ effector NPCs density as well as higher expression of the MIF/ACKR3 signaling in areas where these two cell types were neighbors.</p></div><div><h3>Conclusions</h3><p>These data suggest that ECMO-neutrophil promotes IDD progression by their communication with NPCs via the MIF/ACKR3 axis, which may shed light on therapeutic strategies.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"272 ","pages":"Pages 1-18"},"PeriodicalIF":7.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141187240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glyburide confers neuroprotection against age-related macular degeneration (AMD)","authors":"Emilie Picard ,&nbsp;Jenny Youale ,&nbsp;Max J. Hyman ,&nbsp;Edward Xie ,&nbsp;Seiki Achiedo ,&nbsp;Gabriel T. Kaufmann ,&nbsp;John Moir ,&nbsp;Alejandra Daruich ,&nbsp;Patricia Crisanti ,&nbsp;Alicia Torriglia ,&nbsp;Michel Polak ,&nbsp;Francine Behar-Cohen ,&nbsp;Dimitra Skondra ,&nbsp;Marianne Berdugo","doi":"10.1016/j.trsl.2024.05.002","DOIUrl":"10.1016/j.trsl.2024.05.002","url":null,"abstract":"<div><p>Glyburide, a sulfonylurea drug used to treat type 2 diabetes, boasts neuroprotective effects by targeting the sulfonylurea receptor 1 (SUR1) and associated ion channels in various cell types, including those in the central nervous system and the retina. Previously, we demonstrated that glyburide therapy improved retinal function and structure in a rat model of diabetic retinopathy. In the present study, we explore the application of glyburide in non-neovascular (“dry”) age-related macular degeneration (AMD), another progressive disease characterized by oxidative stress-induced damage and neuroinflammation that trigger cell death in the retina. We show that glyburide administration to a human cone cell line confers protection against oxidative stress, inflammasome activation, and apoptosis. To corroborate our <em>in vitro</em> results, we also conducted a case-control study, controlling for AMD risk factors and other diabetes medications. It showed that glyburide use in patients reduces the odds of new-onset dry AMD. A positive dose-response relationship is observed from this analysis, in which higher cumulative doses of glyburide further reduce the odds of new-onset dry AMD. In the quest for novel therapies for AMD, glyburide emerges as a promising repurposable drug given its known safety profile. The results from this study provide insights into the multifaceted actions of glyburide and its potential as a neuroprotective agent for retinal diseases; however, further preclinical and clinical studies are needed to validate its therapeutic potential in the context of degenerative retinal disorders such as AMD.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"272 ","pages":"Pages 81-94"},"PeriodicalIF":7.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1931524424000938/pdfft?md5=1984d3a24d6b22414b2ffa65d8e4bd56&pid=1-s2.0-S1931524424000938-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential applications of dual haptoglobin expression in the reclassification and treatment of hepatocellular carcinoma","authors":"Lin Liu ,&nbsp;Siyu Hao ,&nbsp;Shuang Gou ,&nbsp;Xiaolong Tang ,&nbsp;Yao Zhang ,&nbsp;Dan Cai ,&nbsp;Mintao Xiao ,&nbsp;Xinyi Zhang ,&nbsp;Duoli Zhang ,&nbsp;Jing Shen ,&nbsp;Yan Li ,&nbsp;Yu Chen ,&nbsp;Yueshui Zhao ,&nbsp;Shuai Deng ,&nbsp;Xu Wu ,&nbsp;Mingxing Li ,&nbsp;Zhuo Zhang ,&nbsp;Zhangang Xiao ,&nbsp;Fukuan Du","doi":"10.1016/j.trsl.2024.05.008","DOIUrl":"10.1016/j.trsl.2024.05.008","url":null,"abstract":"<div><p>HCC is a malignancy characterized by high incidence and mortality rates. Traditional classifications of HCC primarily rely on tumor morphology, phenotype, and multicellular molecular levels, which may not accurately capture the cellular heterogeneity within the tumor. This study integrates scRNA-seq and bulk RNA-seq to spotlight HP as a critical gene within a subgroup of HCC malignant cells. HP is highly expressed in HCC malignant cells and lowly expressed in T cells. Within malignant cells, elevated HP expression interacts with C3, promoting Th1-type responses via the C3/C3AR1 axis. In T cells, down-regulating HP expression favors the expression of Th1 cell-associated marker genes, potentially enhancing Th1-type responses. Consequently, we developed a \"HP-promoted Th1 response reclassification\" gene set, correlating higher activity scores with improved survival rates in HCC patients. Additionally, four predictive models for neoadjuvant treatment based on HP and C3 expression were established: 1) Low HP and C3 expression with high Th2 cell infiltration; 2) High HP and low C3 expression with high Th2 cell infiltration; 3) High HP and C3 expression with high Th1 cell infiltration; 4) Low HP and high C3 expression with high Th1 cell infiltration. In conclusion, the HP gene selected from the HCC malignant cell subgroup (Malignant_Sub 6) might serve as a potential ally against the tumor by promoting Th1-type immune responses. The establishment of the \"HP-promoted Th1 response reclassification\" gene set offers predictive insights for HCC patient survival prognosis and neoadjuvant treatment efficacy, providing directions for clinical treatments.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"272 ","pages":"Pages 19-40"},"PeriodicalIF":7.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis","authors":"Ruogu Pan ,&nbsp;Zhenjun Zhao ,&nbsp;Dongwei Xu ,&nbsp;Chunlai Li ,&nbsp;Qiang Xia","doi":"10.1016/j.trsl.2024.05.007","DOIUrl":"10.1016/j.trsl.2024.05.007","url":null,"abstract":"<div><p>Hepatocellular carcinoma (HCC) is among the most fatal types of malignancy, with a high prevalence of relapse and limited treatment options. As a critical regulator of ferroptosis and redox homeostasis, glutathione peroxidase 4 (<em>GPX4</em>) is commonly upregulated in HCC and is hypothesized to facilitate cancer metastasis, but this has not been fully explored in HCC. Here, we report that up-regulated <em>GPX4</em> expression in HCC is strongly associated with tumor metastasis. FACS-based <em>in vivo</em> and <em>in vitro</em> analysis revealed that a cell subpopulation featuring lower cellular reactive oxygen species levels and ferroptosis resistance were involved in <em>GPX4</em>-mediated HCC metastasis. Mechanistically, <em>GPX4</em> overexpressed in HCC tumor cells was enriched in the nucleus and transcriptionally silenced <em>GRHL3</em> expression, thereby activating PTEN/PI3K/AKT signaling and promoting HCC metastasis. Functional studies demonstrated that GPX4 amino acids 110–145 are a binding site that interacts with the <em>GRHL3</em> promoter. As AKT is a downstream target of GPX4, we combined the AKT inhibitor, AKT-IN3, with lenvatinib to effectively inhibit HCC tumor cell metastasis. Overall, these results indicate that the GPX4/GRHL3/PTEN/PI3K/AKT axis controls HCC cell metastasis and lenvatinib combined with AKT-IN3 represents a potential therapeutic strategy for patients with metastatic HCC.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"271 ","pages":"Pages 79-92"},"PeriodicalIF":7.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141130819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progesterone receptor impairs immune respond and down-regulates sensitivity to anti-LAG3 in breast cancer","authors":"Yunxiao Xiao ,&nbsp;Peng Zheng ,&nbsp;Wenjie Xu ,&nbsp;Zhenghao Wu,&nbsp;Ximeng Zhang,&nbsp;Rong Wang,&nbsp;Tao Huang,&nbsp;Jie Ming","doi":"10.1016/j.trsl.2024.05.001","DOIUrl":"https://doi.org/10.1016/j.trsl.2024.05.001","url":null,"abstract":"<div><h3>Background</h3><p>Progesterone receptor (PR) serves as a crucial prognostic and predictive marker in breast cancer. Nonetheless, the interplay between PR and the tumor immune microenvironment remains inadequately understood. This investigation employs bioinformatics analyses, mouse models, and clinical specimens to elucidate the impact of PR on immune microenvironment and identify potential targets for immunotherapy, furnishing valuable guidance for clinical practice.</p></div><div><h3>Methods</h3><p>Analysis of immune infiltration score by Xcell between PR-positive and PR-negative breast cancer tumors. Construction of overexpression mouse progesterone receptor (mPgr) EMT-6 cell was to explore the tumor immune microenvironment. Furthermore, anti- Lymphocyte-activation gene 3 (LAG3) therapy aimed to investigate whether PR could influence the effectiveness of immune treatments.</p></div><div><h3>Results</h3><p>Overexpression mPgr inhibited tumor growth in vitro, but promoted tumor growth in Balb/c mouse. Flow cytometry showed that the proportion and cytotoxicity of CD8⁺T cells in tumor of overexpressing mPgr group were significantly reduced. The significant reduction in overexpressing mPgr group was found in the proportions of LAG3⁺CD8⁺ T cells and LAG3⁺ Treg T cells. Anti-LAG3 treatment resulted in reduced tumor growth in EV group mouse rather than in overexpressing mPgr group. Patents derived tumor fragment (PDTF) also showed higher anti-tumor ability of CD3⁺T cell in patents’ tumor with PR &lt;20% after anti-human LAG3 treatment in vitro.</p></div><div><h3>Conclusions</h3><p>The mPgr promotes tumor growth by downregulating the infiltration and function of cytotoxic cell. LAG3 may be a target of ER-positive breast cancer immunotherapy. The high expression of PR hinders the sensitivity to anti-LAG3 treatment.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"271 ","pages":"Pages 68-78"},"PeriodicalIF":7.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1931524424000926/pdfft?md5=32accbe567bea1af96c8c6a26fc75d23&pid=1-s2.0-S1931524424000926-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141095431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}