Sara Egea-Rodriguez, Renáta Váraljai, Thierry M. Nordmann, Restuan Lubis, Manuel Philip, Florian Rambow, Alexander Roesch, Michael Flaig, Susanne Horn, Raphael Stoll, Fang Zhao, Annette Paschen, Bert Klebl, Ian D. Hickson, Dirk Schadendorf, Matthias Mann, Iris Helfrich
<div> <section> <h3> Background</h3> <p>Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ-like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains unclear.</p> </section> <section> <h3> Methods</h3> <p>We analysed whole exome and bulk RNA sequencing data from a pan-cancer cohort of 25 775 patients and cutaneous melanoma cohorts (untreated: <i>n</i> = 471, anti-progressive disease [PD]-1 treated: <i>n</i> = 212). <i>RECQL4</i> copy number variations and expression levels were assessed for patient outcomes. We performed gene set enrichment analysis to identify RECQL4-dependent signalling pathways and explored the association between <i>RECQL4</i> levels and immunoscores. We evaluated the interplay of ICI response and <i>RECQL4</i> expression in melanoma cohorts of 95 responders and 85 non-responders prior to and after ICI-targeted therapy and tested the prognostic power of <i>RECQL4</i>. Finally, we generated genetically engineered RECQL4 variants and conducted comprehensive multi-omic profiling, employing techniques such as liquid chromatography with tandem mass spectrometry, to elucidate mechanistic insights.</p> </section> <section> <h3> Results</h3> <p>We identified RECQL4 as a critical negative regulator of poor prognosis and response to ICI therapy, but also demonstrated its suitability as an independent biomarker in melanoma. High tumour purity and limited signatures of tumour immunogenicity associated with response to anti-PD-1 correlated with high RECQL4 activity. We found alterations in the secretion profile of immune regulatory factors and immune-related pathways robustly suppressed in tumours with high <i>RECQL4</i> levels, underscoring its crucial role in fostering immune evasion. Mechanistically, we identified RECQL4-mediated regulation of major histocompatibility complex class II molecule expression and uncovered class II major histocompatibility complex transactivator as a mediator bridging this regulation.</p> </section> <section> <h3> Conclusions</h3> <p>Our findings unraveled the pivotal role of RECQL4 in immune modulation and its potential as both a predictive biomarker and therapeutic target for optimising immunotherapeutic strategies across various cancer types.</p> </section> <section> <h
{"title":"RECQL4 affects MHC class II-mediated signalling and favours an immune-evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma","authors":"Sara Egea-Rodriguez, Renáta Váraljai, Thierry M. Nordmann, Restuan Lubis, Manuel Philip, Florian Rambow, Alexander Roesch, Michael Flaig, Susanne Horn, Raphael Stoll, Fang Zhao, Annette Paschen, Bert Klebl, Ian D. Hickson, Dirk Schadendorf, Matthias Mann, Iris Helfrich","doi":"10.1002/ctm2.70094","DOIUrl":"10.1002/ctm2.70094","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ-like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed whole exome and bulk RNA sequencing data from a pan-cancer cohort of 25 775 patients and cutaneous melanoma cohorts (untreated: <i>n</i> = 471, anti-progressive disease [PD]-1 treated: <i>n</i> = 212). <i>RECQL4</i> copy number variations and expression levels were assessed for patient outcomes. We performed gene set enrichment analysis to identify RECQL4-dependent signalling pathways and explored the association between <i>RECQL4</i> levels and immunoscores. We evaluated the interplay of ICI response and <i>RECQL4</i> expression in melanoma cohorts of 95 responders and 85 non-responders prior to and after ICI-targeted therapy and tested the prognostic power of <i>RECQL4</i>. Finally, we generated genetically engineered RECQL4 variants and conducted comprehensive multi-omic profiling, employing techniques such as liquid chromatography with tandem mass spectrometry, to elucidate mechanistic insights.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified RECQL4 as a critical negative regulator of poor prognosis and response to ICI therapy, but also demonstrated its suitability as an independent biomarker in melanoma. High tumour purity and limited signatures of tumour immunogenicity associated with response to anti-PD-1 correlated with high RECQL4 activity. We found alterations in the secretion profile of immune regulatory factors and immune-related pathways robustly suppressed in tumours with high <i>RECQL4</i> levels, underscoring its crucial role in fostering immune evasion. Mechanistically, we identified RECQL4-mediated regulation of major histocompatibility complex class II molecule expression and uncovered class II major histocompatibility complex transactivator as a mediator bridging this regulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings unraveled the pivotal role of RECQL4 in immune modulation and its potential as both a predictive biomarker and therapeutic target for optimising immunotherapeutic strategies across various cancer types.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982844","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}
Thyroid cancer is one of the most common endocrine tumors worldwide, especially among women and the metastatic mechanism of papillary thyroid carcinoma remains poorly understood.
Methods
Thyroid cancer tissue samples were obtained for single-cell RNA-sequencing and spatial transcriptomics, aiming to intratumoral and antimetastatic heterogeneity of advanced PTC. The functions of APOE in PTC cell proliferation and invasion were confirmed through in vivo and in vitro assays. Pseudotime analysis and CellChat were performed to explore the the molecular mechanisms of the APOE in PTC progression.
Results
We identified a subpopulation of tumor cells with lower expression levels of APOE, associated with advanced stages of PTC and cervical metastasis. APOE overexpression significantly reduced tumor cell proliferation and invasion, both in vitro and in vivo, by activating the ABCA1-LXR axis. APOE− tumor cells may promote tumor growth by interacting with dendritic cells and CD4+ T cells via CD99- rather than CD6-regulated signaling. We established a machine learning-based scRNA-seq data, 13-gene signature predictive of lymph node metastasis.
Conclusions
We identified a distinct APOE− tumor cell population associated with cervical metastasis and poor prognosis. Our results and models have potential clinical, prognostic, and therapeutic implications for advanced PTC.
Key points
A subpopulation of tumor cells with lower expression levels of APOE was strongly associated with more advanced stages and metastasis of PTC.
APOE-negative (APOE−) cellsoverall exhibited weaker interactions with immune cells.
A machine-learning bioinformatics model based on scRNA-seq data of in-situ thyroid cancer tissue was established to predict lymph node metastasis.
{"title":"Single-cell RNA-sequencing and spatial transcriptomic analysis reveal a distinct population of APOE− cells yielding pathological lymph node metastasis in papillary thyroid cancer","authors":"Guohui Xiao, Rongli Xie, Jianhua Gu, Yishu Huang, Min Ding, Dongjie Shen, Jiqi Yan, Jianming Yuan, Qiong Yang, Wen He, Siyu Xiao, Haizhen Chen, Dan Xu, Jian Wu, Jian Fei","doi":"10.1002/ctm2.70172","DOIUrl":"10.1002/ctm2.70172","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Thyroid cancer is one of the most common endocrine tumors worldwide, especially among women and the metastatic mechanism of papillary thyroid carcinoma remains poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Thyroid cancer tissue samples were obtained for single-cell RNA-sequencing and spatial transcriptomics, aiming to intratumoral and antimetastatic heterogeneity of advanced PTC. The functions of <i>APOE</i> in PTC cell proliferation and invasion were confirmed through in vivo and in vitro assays. Pseudotime analysis and CellChat were performed to explore the the molecular mechanisms of the <i>APOE</i> in PTC progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified a subpopulation of tumor cells with lower expression levels of <i>APOE</i>, associated with advanced stages of PTC and cervical metastasis. <i>APOE</i> overexpression significantly reduced tumor cell proliferation and invasion, both in vitro and in vivo, by activating the <i>ABCA1-LXR</i> axis. <i>APOE<sup>−</sup></i> tumor cells may promote tumor growth by interacting with dendritic cells and CD4<sup>+</sup> T cells via <i>CD99</i>- rather than CD6-regulated signaling. We established a machine learning-based scRNA-seq data, 13-gene signature predictive of lymph node metastasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified a distinct <i>APOE<sup>−</sup></i> tumor cell population associated with cervical metastasis and poor prognosis. Our results and models have potential clinical, prognostic, and therapeutic implications for advanced PTC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>A subpopulation of tumor cells with lower expression levels of <i>APOE</i> was strongly associated with more advanced stages and metastasis of PTC.</li>\u0000 \u0000 <li><i>APOE</i>-negative (<i>APOE</i><sup>−</sup>) cellsoverall exhibited weaker interactions with immune cells.</li>\u0000 \u0000 <li>A machine-learning bioinformatics model based on scRNA-seq data of in-situ thyroid cancer tissue was established to predict lymph node metastasis.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982852","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}
Zhiyao Wei, Cheng Cui, Zixuan Li, Jianping Li, Yibing Shao, Jizheng Wang, Jincheng Guo, Lei Song
<p>Dear Editor,</p><p>Intracoronary thrombosis, resulting from the rupture or erosion of atherosclerotic plaques, is the main cause of acute myocardial infarction (AMI). The role of immune cells in thrombosis has garnered attention as a central contributor to this catastrophic event.<span><sup>1</sup></span> To further our understanding, we conducted single-cell RNA sequencing to picture a cellular atlas of aspired intracoronary thrombus.</p><p>Our dataset comprised a total of 10 456 cells, and a median of 2786 genes were detected per cell (Figure 1). Unsupervised clustering revealed that the largest part of cells in the intracoronary thrombus were monocytes (29.3%). We further subclustered monocytes and identified eight subclusters (Figure 2A). Cluster 6 was identified as conventional dendritic cells, for the high expression levels of HLA-DRB1 and HLA-DRA. The remaining clusters were categorized based on the relative expression levels of CD14 and FCGR3A, leading to three classifications: classical (CD14<sup>++</sup>/FCGR3A<sup>−</sup>; clusters 0, 2, 4), intermediate (CD14<sup>++</sup>/FCGR3A<sup>+</sup>; clusters 1, 3) and non-classical monocytes (CD14<sup>+</sup>/FCGR3A<sup>++</sup>; clusters 5, 7) (Figure 2B,C). Marker genes and functional heterogeneity for each cluster are presented in Figure 2D,E. Besides, among the monocytes, 14 modules of co-regulated genes were identified by weighted gene co-expression network analysis (WGCNA) (Figure 2F).</p><p>Classical monocytes comprised the largest proportion of the monocyte population (60.1%) and exhibited diverse functions. Cluster 0 (30.1%) demonstrated significant activation in response to non-infectious stimuli during AMI, characterized by elevated expression levels of NLRP3, IL-1B and NFKBIA. Module brown (TNF and NF-kappa signalling pathway) displayed a strong correlation with cluster 0 (Figure S1A). Cluster 2 (21.8%) displayed heightened expression of inflammatory mediators including S100A9, S100A8, CTSS and phagocytosis receptor CD36 (Figure 2G). Figure 2H,I proved its presentation. This cluster had a strong correlation with module tan, which is linked to phagosome and leukocyte trans-endothelial migration (Figure S2B). Cluster 4 (6.6%) exhibited elevated expression of T cell activation genes (CD247, NKG7, GNLY) and was associated with module black (nature killer [NK]-mediated cytotoxicity) (Figure S1C).</p><p>Intermediate monocytes represented 35.7% of the total monocyte population and comprised two distinct clusters. Cluster 1 (26.9%) showed a pro-fibrotic and anti-inflammatory profile, characterized by high expression levels of genes associated with fibrosis (FN1, SPP1), cardiac protection (CTSL, ANGPTL4), T cell activation (ALCAM), oxidized low-density lipoprotein-induced cell injury (ANGPTL4) and phagocytosis (MERTK). Four modules were predominantly expressed in cluster 1. Notably, module pink facilitated substrate adhesion-dependent cell spreading and endocytosis (Figure S1D), while m
{"title":"Major cell types in the coronary thrombosis of acute myocardial infarction patients revealed by scRNA-seq","authors":"Zhiyao Wei, Cheng Cui, Zixuan Li, Jianping Li, Yibing Shao, Jizheng Wang, Jincheng Guo, Lei Song","doi":"10.1002/ctm2.70181","DOIUrl":"10.1002/ctm2.70181","url":null,"abstract":"<p>Dear Editor,</p><p>Intracoronary thrombosis, resulting from the rupture or erosion of atherosclerotic plaques, is the main cause of acute myocardial infarction (AMI). The role of immune cells in thrombosis has garnered attention as a central contributor to this catastrophic event.<span><sup>1</sup></span> To further our understanding, we conducted single-cell RNA sequencing to picture a cellular atlas of aspired intracoronary thrombus.</p><p>Our dataset comprised a total of 10 456 cells, and a median of 2786 genes were detected per cell (Figure 1). Unsupervised clustering revealed that the largest part of cells in the intracoronary thrombus were monocytes (29.3%). We further subclustered monocytes and identified eight subclusters (Figure 2A). Cluster 6 was identified as conventional dendritic cells, for the high expression levels of HLA-DRB1 and HLA-DRA. The remaining clusters were categorized based on the relative expression levels of CD14 and FCGR3A, leading to three classifications: classical (CD14<sup>++</sup>/FCGR3A<sup>−</sup>; clusters 0, 2, 4), intermediate (CD14<sup>++</sup>/FCGR3A<sup>+</sup>; clusters 1, 3) and non-classical monocytes (CD14<sup>+</sup>/FCGR3A<sup>++</sup>; clusters 5, 7) (Figure 2B,C). Marker genes and functional heterogeneity for each cluster are presented in Figure 2D,E. Besides, among the monocytes, 14 modules of co-regulated genes were identified by weighted gene co-expression network analysis (WGCNA) (Figure 2F).</p><p>Classical monocytes comprised the largest proportion of the monocyte population (60.1%) and exhibited diverse functions. Cluster 0 (30.1%) demonstrated significant activation in response to non-infectious stimuli during AMI, characterized by elevated expression levels of NLRP3, IL-1B and NFKBIA. Module brown (TNF and NF-kappa signalling pathway) displayed a strong correlation with cluster 0 (Figure S1A). Cluster 2 (21.8%) displayed heightened expression of inflammatory mediators including S100A9, S100A8, CTSS and phagocytosis receptor CD36 (Figure 2G). Figure 2H,I proved its presentation. This cluster had a strong correlation with module tan, which is linked to phagosome and leukocyte trans-endothelial migration (Figure S2B). Cluster 4 (6.6%) exhibited elevated expression of T cell activation genes (CD247, NKG7, GNLY) and was associated with module black (nature killer [NK]-mediated cytotoxicity) (Figure S1C).</p><p>Intermediate monocytes represented 35.7% of the total monocyte population and comprised two distinct clusters. Cluster 1 (26.9%) showed a pro-fibrotic and anti-inflammatory profile, characterized by high expression levels of genes associated with fibrosis (FN1, SPP1), cardiac protection (CTSL, ANGPTL4), T cell activation (ALCAM), oxidized low-density lipoprotein-induced cell injury (ANGPTL4) and phagocytosis (MERTK). Four modules were predominantly expressed in cluster 1. Notably, module pink facilitated substrate adhesion-dependent cell spreading and endocytosis (Figure S1D), while m","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968848","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}
<p>Dear Editor,</p><p>Intrahepatic cholangiocarcinoma (ICC) is a malignant tumour originating from the epithelial cells of the intrahepatic bile ducts. In recent years, its incidence has shown an upward trend globally. Notably, hepatitis B virus (HBV) infection is one of the significant risk factors for ICC.<span><sup>1</sup></span> Despite significant advancements in medical imaging and molecular biology technologies, predicting the prognosis of HBV-associated ICC patients remains challenging. One major reason for this challenge is the complex interactions between HBV infection, genetic mutations and tumour behaviour, which increase the uncertainty of prognosis predictions. As a result, traditional single indicators are insufficient for comprehensively assessing patient outcomes. Radiomics is a technology that extracts a large number of quantitative features from medical images, capturing the spatial structure and morphological changes of tumours.<span><sup>2</sup></span> Genomics, on the other hand, focuses on deciphering DNA sequence information, revealing the contributions of genetic variations to disease development. This study aims to develop and validate a predictive model that integrates radiomic features with genomic information. By doing so, it seeks to overcome the limitations of existing biomarkers, better meet the needs for personalised treatment of HBV-associated ICC patients and provide valuable references for future research and clinical practice.</p><p>A total of 389 intrahepatic cholangiocarcinoma (ICC) patients were retrospectively included and divided into a training cohort (210 patients), an internal validation cohort (90 patients) and an external validation cohort (89 patients). Table S1 displayed the clinical and imaging characteristics. The results showed that most clinical characteristics did not differ significantly between the groups, including age (<i>p</i> = .188), gender distribution (<i>p</i> = .456), the proportion of ferritin ≤323 (<i>p</i> = .282), the proportion of high PIVKA-II (<i>p</i> = .988), HBV infection rate (<i>p</i> = .158), perineural invasion (<i>p</i> = .294) and AJCC 8th edition Classification of Malignant Tumors (TNM) staging (<i>p</i> = .455). The only characteristic that showed a statistically significant difference was the presence of vessel cancer embolus (VCE), with the training cohort (19.8%) significantly higher than the internal validation cohort (7.4%) and the external validation cohort (10.4%), <i>p</i> = .044. There were no extreme biases between the three cohorts in baseline data. Figure 1 showed the flow diagram of the exclusion criteria of the ICC radiomic datasets. A total of 972 features of magnetic resonance imaging (MRI) images were extracted from the ROIs using the PyRadiomics Python package,<span><sup>3</sup></span> and those with ICC values > 0.8 on both intra- and inter-observer agreement analyses were retained. Table S2 comprehensively summarised the essential patient dem
{"title":"Predictive nomogram integrating radiomics and multi-omics for improved prognosis-model in cholangiocarcinoma","authors":"Yunlu Jia, Mingyu Wan, Yifei Shen, Junli Wang, Xiao Luo, Mengye He, Ruiliang Bai, Wenbo Xiao, Xiaochen Zhang, Jian Ruan","doi":"10.1002/ctm2.70171","DOIUrl":"10.1002/ctm2.70171","url":null,"abstract":"<p>Dear Editor,</p><p>Intrahepatic cholangiocarcinoma (ICC) is a malignant tumour originating from the epithelial cells of the intrahepatic bile ducts. In recent years, its incidence has shown an upward trend globally. Notably, hepatitis B virus (HBV) infection is one of the significant risk factors for ICC.<span><sup>1</sup></span> Despite significant advancements in medical imaging and molecular biology technologies, predicting the prognosis of HBV-associated ICC patients remains challenging. One major reason for this challenge is the complex interactions between HBV infection, genetic mutations and tumour behaviour, which increase the uncertainty of prognosis predictions. As a result, traditional single indicators are insufficient for comprehensively assessing patient outcomes. Radiomics is a technology that extracts a large number of quantitative features from medical images, capturing the spatial structure and morphological changes of tumours.<span><sup>2</sup></span> Genomics, on the other hand, focuses on deciphering DNA sequence information, revealing the contributions of genetic variations to disease development. This study aims to develop and validate a predictive model that integrates radiomic features with genomic information. By doing so, it seeks to overcome the limitations of existing biomarkers, better meet the needs for personalised treatment of HBV-associated ICC patients and provide valuable references for future research and clinical practice.</p><p>A total of 389 intrahepatic cholangiocarcinoma (ICC) patients were retrospectively included and divided into a training cohort (210 patients), an internal validation cohort (90 patients) and an external validation cohort (89 patients). Table S1 displayed the clinical and imaging characteristics. The results showed that most clinical characteristics did not differ significantly between the groups, including age (<i>p</i> = .188), gender distribution (<i>p</i> = .456), the proportion of ferritin ≤323 (<i>p</i> = .282), the proportion of high PIVKA-II (<i>p</i> = .988), HBV infection rate (<i>p</i> = .158), perineural invasion (<i>p</i> = .294) and AJCC 8th edition Classification of Malignant Tumors (TNM) staging (<i>p</i> = .455). The only characteristic that showed a statistically significant difference was the presence of vessel cancer embolus (VCE), with the training cohort (19.8%) significantly higher than the internal validation cohort (7.4%) and the external validation cohort (10.4%), <i>p</i> = .044. There were no extreme biases between the three cohorts in baseline data. Figure 1 showed the flow diagram of the exclusion criteria of the ICC radiomic datasets. A total of 972 features of magnetic resonance imaging (MRI) images were extracted from the ROIs using the PyRadiomics Python package,<span><sup>3</sup></span> and those with ICC values > 0.8 on both intra- and inter-observer agreement analyses were retained. Table S2 comprehensively summarised the essential patient dem","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969018","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}
<p>Lung cancer remains the leading carcinoma type in morbidity and mortality, distinguished by one of the lowest five-year survival rates. Despite improvements with incorporation of immune checkpoint therapy in certain contexts, systemic immune-related adverse events and the immunosuppressive tumour microenvironment(TME) constrain their effectiveness. Consequently, cytokines have emerged as a next-generation immunotherapy that can convert immunologically ‘cold’ tumours into ‘hot’ ones.<span><sup>1</sup></span> Interleukin-12 (IL12), a potent cytokine, has demonstrated significant efficacy in stimulating interferon-γ (IFN-γ) production and enhancing the cytolytic activity of immune cells. However, current research on IL12 normally focuses on intratumour injection due to the off-target-induced toxicity in systemic delivery.<span><sup>2</sup></span> Therefore, developing targeted and localised delivery platforms for IL12 is critical for deep-organ tumours, especially lung cancer. Our research introduces IL12 messenger RNA (mRNA)-loaded exosomes (IL12-Exo), which are directly delivered into the lung TME through inhalation, providing a groundbreaking approach to lung cancer immunotherapy.<span><sup>3</sup></span></p><p>The efficacy and safety of IL12 therapy hinge on its successful local delivery, which depends on enhanced targeting to the lung tumours and minimised leakage into the blood circulation and off-target organs. The mRNA of IL12 serves as an ideal delivery cargo, with its intratumoural delivery already advancing to clinical trials since the mRNA ensures local translation.<span><sup>4</sup></span> Additionally, extracellular vesicles, especially exosomes, are natural vesicles derived from cells and offer tremendous therapeutic potential through their inherent cargos or external mRNA delivery platforms.<span><sup>5-7</sup></span> Notably, we have harnessed lung spheroid cells as a novel source of therapeutic exosomes,<span><sup>8-10</sup></span> now in a first-in-man clinical trial for patients with idiopathic pulmonary fibrosis. We have also innovated various exosome-mediated delivery systems for lung-specific diseases, including COVID-19,<span><sup>7, 11, 12</sup></span> demonstrating the effectiveness of inhalation as a non-invasive and localised administration route.<span><sup>8, 13-19</sup></span></p><p>Upon nebulised inhalation in a mouse model with lung tumours, IL12-Exo achieved targeted delivery and localised expression of IL12 cytokine (Figure 1). Neutralised inhalation delivery of IL12-Exo showed superior accumulation in the lung compared to other off-target organs, and the exosome platform exhibited a specific affinity for tumour cells over the IL12 mRNA-loaded liposome (IL12-Lipo) control. These findings align with our previous research indicating superior delivery of mRNA and protein in healthy lungs when encapsulated in exosomes rather than liposomes.<span><sup>20</sup></span> As expected, the enhanced localisation led to susta
{"title":"Translational inhalable extracellular vesicle-based mRNA therapy for the treatment of lung cancer","authors":"Mengrui Liu, Brian Henick, Ke Cheng","doi":"10.1002/ctm2.70186","DOIUrl":"10.1002/ctm2.70186","url":null,"abstract":"<p>Lung cancer remains the leading carcinoma type in morbidity and mortality, distinguished by one of the lowest five-year survival rates. Despite improvements with incorporation of immune checkpoint therapy in certain contexts, systemic immune-related adverse events and the immunosuppressive tumour microenvironment(TME) constrain their effectiveness. Consequently, cytokines have emerged as a next-generation immunotherapy that can convert immunologically ‘cold’ tumours into ‘hot’ ones.<span><sup>1</sup></span> Interleukin-12 (IL12), a potent cytokine, has demonstrated significant efficacy in stimulating interferon-γ (IFN-γ) production and enhancing the cytolytic activity of immune cells. However, current research on IL12 normally focuses on intratumour injection due to the off-target-induced toxicity in systemic delivery.<span><sup>2</sup></span> Therefore, developing targeted and localised delivery platforms for IL12 is critical for deep-organ tumours, especially lung cancer. Our research introduces IL12 messenger RNA (mRNA)-loaded exosomes (IL12-Exo), which are directly delivered into the lung TME through inhalation, providing a groundbreaking approach to lung cancer immunotherapy.<span><sup>3</sup></span></p><p>The efficacy and safety of IL12 therapy hinge on its successful local delivery, which depends on enhanced targeting to the lung tumours and minimised leakage into the blood circulation and off-target organs. The mRNA of IL12 serves as an ideal delivery cargo, with its intratumoural delivery already advancing to clinical trials since the mRNA ensures local translation.<span><sup>4</sup></span> Additionally, extracellular vesicles, especially exosomes, are natural vesicles derived from cells and offer tremendous therapeutic potential through their inherent cargos or external mRNA delivery platforms.<span><sup>5-7</sup></span> Notably, we have harnessed lung spheroid cells as a novel source of therapeutic exosomes,<span><sup>8-10</sup></span> now in a first-in-man clinical trial for patients with idiopathic pulmonary fibrosis. We have also innovated various exosome-mediated delivery systems for lung-specific diseases, including COVID-19,<span><sup>7, 11, 12</sup></span> demonstrating the effectiveness of inhalation as a non-invasive and localised administration route.<span><sup>8, 13-19</sup></span></p><p>Upon nebulised inhalation in a mouse model with lung tumours, IL12-Exo achieved targeted delivery and localised expression of IL12 cytokine (Figure 1). Neutralised inhalation delivery of IL12-Exo showed superior accumulation in the lung compared to other off-target organs, and the exosome platform exhibited a specific affinity for tumour cells over the IL12 mRNA-loaded liposome (IL12-Lipo) control. These findings align with our previous research indicating superior delivery of mRNA and protein in healthy lungs when encapsulated in exosomes rather than liposomes.<span><sup>20</sup></span> As expected, the enhanced localisation led to susta","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969337","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}
<div> <section> <h3> Background</h3> <p>House dust mite (HDM) is the leading allergen for allergic rhinitis (AR). Although allergic sensitisation by inhaled allergens renders susceptible individuals prone to developing AR, the molecular mechanisms driving this process remain incompletely elucidated.</p> </section> <section> <h3> Objective</h3> <p>This study aimed to elucidate the molecular mechanisms underlying HDM-induced AR.</p> </section> <section> <h3> Methods</h3> <p>We examined the expression of cytidine/uridine monophosphate kinase 2 (CMPK2), STING and the NLRP3 inflammasome in both AR patients and mice. Additionally, we investigated the role of CMPK2 and STING in the activation of the NLRP3 inflammasome in AR.</p> </section> <section> <h3> Results</h3> <p>The expression of CMPK2, STING and the NLRP3 inflammasome was significantly increased in the nasal mucosa of AR patients compared to non-AR controls. A positive correlation was found between CMPK2 expression and the levels of STING, NLRP3, ASC, CASP1 and IL-1β. HDM treatment up-regulated the expression of CMPK2, and CMPK2 overexpression enhanced NLRP3 inflammasome activation in human nasal epithelial cells (HNEPCs). Additionally, mitochondrial reactive oxygen species (mtROS) production following HDM exposure contributed to mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA), which activated the cyclic GMP-AMP synthase (cGAS)-STING pathway. Remarkably, depletion of mtDNA or inhibition of STING signalling reduced HDM-induced NLRP3 inflammasome activation in HNEPCs. In vivo, genetic knockout of CMPK2 or STING alleviated NLRP3 inflammasome activation and ameliorated clinical symptoms of AR in mice.</p> </section> <section> <h3> Conclusions</h3> <p>Our results suggest that HDM promotes the activation of NLRP3 inflammasome through the up-regulation of CMPK2 and ensuing mtDNA-STING signalling pathway, hence revealing additional therapeutic target for AR.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li> <p>Cytidine/uridine monophosphate kinase 2 (CMPK2) expression is up-regulated in the nasal mucosa of patients and mice with allergic rhinitis (AR).</p> </li> <li> <p>CMPK2 caused NLRP3 inflamma
{"title":"CMPK2 promotes NLRP3 inflammasome activation via mtDNA-STING pathway in house dust mite-induced allergic rhinitis","authors":"YaoMing Zheng, YaDong Xie, JiaYing Li, YuJie Cao, Min Li, Qing Cao, MiaoMiao Han, HongFei Lou, YiLai Shu, Hui Xiao, HuaBin Li","doi":"10.1002/ctm2.70180","DOIUrl":"10.1002/ctm2.70180","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>House dust mite (HDM) is the leading allergen for allergic rhinitis (AR). Although allergic sensitisation by inhaled allergens renders susceptible individuals prone to developing AR, the molecular mechanisms driving this process remain incompletely elucidated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aimed to elucidate the molecular mechanisms underlying HDM-induced AR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We examined the expression of cytidine/uridine monophosphate kinase 2 (CMPK2), STING and the NLRP3 inflammasome in both AR patients and mice. Additionally, we investigated the role of CMPK2 and STING in the activation of the NLRP3 inflammasome in AR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The expression of CMPK2, STING and the NLRP3 inflammasome was significantly increased in the nasal mucosa of AR patients compared to non-AR controls. A positive correlation was found between CMPK2 expression and the levels of STING, NLRP3, ASC, CASP1 and IL-1β. HDM treatment up-regulated the expression of CMPK2, and CMPK2 overexpression enhanced NLRP3 inflammasome activation in human nasal epithelial cells (HNEPCs). Additionally, mitochondrial reactive oxygen species (mtROS) production following HDM exposure contributed to mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA), which activated the cyclic GMP-AMP synthase (cGAS)-STING pathway. Remarkably, depletion of mtDNA or inhibition of STING signalling reduced HDM-induced NLRP3 inflammasome activation in HNEPCs. In vivo, genetic knockout of CMPK2 or STING alleviated NLRP3 inflammasome activation and ameliorated clinical symptoms of AR in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results suggest that HDM promotes the activation of NLRP3 inflammasome through the up-regulation of CMPK2 and ensuing mtDNA-STING signalling pathway, hence revealing additional therapeutic target for AR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Cytidine/uridine monophosphate kinase 2 (CMPK2) expression is up-regulated in the nasal mucosa of patients and mice with allergic rhinitis (AR).</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>CMPK2 caused NLRP3 inflamma","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968843","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}
Min-Jun Baek, Sang Min Lee, Dae-Duk Kim, Jae-Young Lee
<p>Photodynamic therapy (PDT), which leverages reactive oxygen species to eliminate cancer cells, offers a promising alternative to conventional cancer treatments. By utilising light-activated photosensitizers (PSs), PDT achieves precise tumour targeting while minimising damage to surrounding healthy tissues. This targeted approach positions PDT as a potential replacement for surgery and radiation therapy in selected cases. However, the clinical utility of PDT in managing solid tumours remains constrained by several critical challenges, including suboptimal tumour accumulation and limited penetration of PSs into tumour tissues.<span><sup>1</sup></span> These barriers often lead to incomplete tumour remission, rendering PDT less effective compared to traditional therapies. Addressing these limitations requires innovative PS delivery systems to enhance the performance of PDT.</p><p>Nanoparticle (NP)-based delivery systems have emerged as a promising approach to overcome these obstacles. By leveraging their unique properties, NPs can improve the solubility, stability and tumour selectivity of PSs. However, NP-based approaches often fail to achieve satisfactory outcomes due to poor penetration of NPs into tumour tissues.<span><sup>2</sup></span> Overcoming these challenges requires innovative tumour-targeted delivery systems that enhance both the specificity and penetrability of NPs.</p><p>Our recent study introduced photobleaching-mediated charge-convertible zwitterionic near-infrared NPs (P-ZWNIR NPs), representing a transformative innovation in nano-phototheranostics.<span><sup>3</sup></span> These multifunctional NPs address critical limitations of PDT and nanotherapeutics by integrating advanced design principles to enhance targeting and penetration in solid tumours. P-ZWNIR NPs feature a photobleaching-mediated charge conversion mechanism. Initially, the NPs are designed to have zwitterionic surface charge to ensure colloidal stability, reduce off-target adsorptions and facilitate tumour-selective accumulation upon intravenous injection. The outer zwitterionic near-infrared (NIR) fluorophore component of the NPs undergoes photobleaching upon exposure to an 808 nm laser, which induces charge conversion to a cationic charge (Figure 1A).</p><p>A key innovation of P-ZWNIR NPs is rapid and efficient charge conversion within tumour tissue, which further facilitates deep tumour penetration. Upon exposure to 808 nm laser, the zwitterionic surface transitions to a cationic state via photooxidative cleavage of the NIR fluorophore component in the NPs. The resulting cationic charge facilitates transcytosis of NPs, enabling them to cross multiple layers of cells in tumour tissue. By promoting active penetration, P-ZWNIR NPs achieved homogeneous distribution of PSs throughout the tumour tissue (Figure 1B).</p><p>In orthotopic rectal tumour-bearing mouse models, intravenous administration of P-ZWNIR NPs resulted in a tumour-to-background ratio as high as 10
{"title":"Breakthroughs in deep tumour penetrating nano-phototheranostics for tumour ablation","authors":"Min-Jun Baek, Sang Min Lee, Dae-Duk Kim, Jae-Young Lee","doi":"10.1002/ctm2.70188","DOIUrl":"10.1002/ctm2.70188","url":null,"abstract":"<p>Photodynamic therapy (PDT), which leverages reactive oxygen species to eliminate cancer cells, offers a promising alternative to conventional cancer treatments. By utilising light-activated photosensitizers (PSs), PDT achieves precise tumour targeting while minimising damage to surrounding healthy tissues. This targeted approach positions PDT as a potential replacement for surgery and radiation therapy in selected cases. However, the clinical utility of PDT in managing solid tumours remains constrained by several critical challenges, including suboptimal tumour accumulation and limited penetration of PSs into tumour tissues.<span><sup>1</sup></span> These barriers often lead to incomplete tumour remission, rendering PDT less effective compared to traditional therapies. Addressing these limitations requires innovative PS delivery systems to enhance the performance of PDT.</p><p>Nanoparticle (NP)-based delivery systems have emerged as a promising approach to overcome these obstacles. By leveraging their unique properties, NPs can improve the solubility, stability and tumour selectivity of PSs. However, NP-based approaches often fail to achieve satisfactory outcomes due to poor penetration of NPs into tumour tissues.<span><sup>2</sup></span> Overcoming these challenges requires innovative tumour-targeted delivery systems that enhance both the specificity and penetrability of NPs.</p><p>Our recent study introduced photobleaching-mediated charge-convertible zwitterionic near-infrared NPs (P-ZWNIR NPs), representing a transformative innovation in nano-phototheranostics.<span><sup>3</sup></span> These multifunctional NPs address critical limitations of PDT and nanotherapeutics by integrating advanced design principles to enhance targeting and penetration in solid tumours. P-ZWNIR NPs feature a photobleaching-mediated charge conversion mechanism. Initially, the NPs are designed to have zwitterionic surface charge to ensure colloidal stability, reduce off-target adsorptions and facilitate tumour-selective accumulation upon intravenous injection. The outer zwitterionic near-infrared (NIR) fluorophore component of the NPs undergoes photobleaching upon exposure to an 808 nm laser, which induces charge conversion to a cationic charge (Figure 1A).</p><p>A key innovation of P-ZWNIR NPs is rapid and efficient charge conversion within tumour tissue, which further facilitates deep tumour penetration. Upon exposure to 808 nm laser, the zwitterionic surface transitions to a cationic state via photooxidative cleavage of the NIR fluorophore component in the NPs. The resulting cationic charge facilitates transcytosis of NPs, enabling them to cross multiple layers of cells in tumour tissue. By promoting active penetration, P-ZWNIR NPs achieved homogeneous distribution of PSs throughout the tumour tissue (Figure 1B).</p><p>In orthotopic rectal tumour-bearing mouse models, intravenous administration of P-ZWNIR NPs resulted in a tumour-to-background ratio as high as 10 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968842","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}
Aneal Khan, Dwayne L. Barber, William M. McKillop, C. Anthony Rupar, Christiane Auray-Blais, Graeme Fraser, Daniel H. Fowler, Alexandra Berger, Ronan Foley, Armand Keating, Michael L. West, Jeffrey A. Medin
<div> <section> <h3> Background</h3> <p>Fabry disease is an X-linked lysosomal storage disorder due to a deficiency of α-galactosidase A (α-gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α-gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs). Overexpression of α-gal A leads to secretion of the hydrolase; which can be taken up and used by uncorrected bystander cells. Gene-augmented HSPCs can circulate and thus provide sustained systemic correction. Interim results from this ‘first-in-the-world’ Canadian FACTs (Fabry Disease Clinical Research and Therapeutics) trial were published in 2021. Herein we report 5-year ‘End-of-Study’ results.</p> </section> <section> <h3> Methods</h3> <p>Five males with classical Fabry disease were treated. Their HSPCs were mobilized, enriched, and transduced with a recombinant lentivirus engineering expression of α-gal A. Autologous transduced cells were infused after conditioning with a nonmyeloablative, reduced dose, melphalan regimen. Safety monitoring was performed. α-Gal A activity was measured in plasma and peripheral blood (PB) leucocytes. Globotriaosylceramide (Gb3) and lyso-Gb3 levels in urine and plasma were assessed by mass spectrometry. qPCR assays measured vector copy number in PB leucocytes. Antibody titers were measured by ELISA. Body weight, blood pressure, urinary protein levels, eGFR, troponin levels, and LVMI were tracked.</p> </section> <section> <h3> Results</h3> <p>Four out of 5 patients went home the same day as their infusions; one was kept overnight for observation. Circulating α-gal A activity was observed at Day 6–8 in each patient following infusion and has remained durable for 5+ years. LV marking of peripheral blood cells has remained durable and polyclonal. All 5 patients were eligible to come off biweekly enzyme therapy; 3 patients did so. Plasma lyso-Gb3 was significantly lower in 4 of 5 patients. There was no sustained elevation of anti-α-gal A antibodies. Patient weight was stable in 4 of the 5 patients. All blood pressures were in the normal range. Kidney symptoms were stabilized in all patients.</p> </section> <section> <h3> Conclusions</h3> <p>This treatment was well tolerated as only two SAEs occurred (during the treatment phase) and only two AEs were reported since 2021. We demonstrate that this therapeutic approach has merit, is durable, and should be explored in a larger clinical trial.</p> </section> <section> <h3> Highlights</h3>
{"title":"Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial","authors":"Aneal Khan, Dwayne L. Barber, William M. McKillop, C. Anthony Rupar, Christiane Auray-Blais, Graeme Fraser, Daniel H. Fowler, Alexandra Berger, Ronan Foley, Armand Keating, Michael L. West, Jeffrey A. Medin","doi":"10.1002/ctm2.70073","DOIUrl":"10.1002/ctm2.70073","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Fabry disease is an X-linked lysosomal storage disorder due to a deficiency of α-galactosidase A (α-gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α-gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs). Overexpression of α-gal A leads to secretion of the hydrolase; which can be taken up and used by uncorrected bystander cells. Gene-augmented HSPCs can circulate and thus provide sustained systemic correction. Interim results from this ‘first-in-the-world’ Canadian FACTs (Fabry Disease Clinical Research and Therapeutics) trial were published in 2021. Herein we report 5-year ‘End-of-Study’ results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Five males with classical Fabry disease were treated. Their HSPCs were mobilized, enriched, and transduced with a recombinant lentivirus engineering expression of α-gal A. Autologous transduced cells were infused after conditioning with a nonmyeloablative, reduced dose, melphalan regimen. Safety monitoring was performed. α-Gal A activity was measured in plasma and peripheral blood (PB) leucocytes. Globotriaosylceramide (Gb3) and lyso-Gb3 levels in urine and plasma were assessed by mass spectrometry. qPCR assays measured vector copy number in PB leucocytes. Antibody titers were measured by ELISA. Body weight, blood pressure, urinary protein levels, eGFR, troponin levels, and LVMI were tracked.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Four out of 5 patients went home the same day as their infusions; one was kept overnight for observation. Circulating α-gal A activity was observed at Day 6–8 in each patient following infusion and has remained durable for 5+ years. LV marking of peripheral blood cells has remained durable and polyclonal. All 5 patients were eligible to come off biweekly enzyme therapy; 3 patients did so. Plasma lyso-Gb3 was significantly lower in 4 of 5 patients. There was no sustained elevation of anti-α-gal A antibodies. Patient weight was stable in 4 of the 5 patients. All blood pressures were in the normal range. Kidney symptoms were stabilized in all patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This treatment was well tolerated as only two SAEs occurred (during the treatment phase) and only two AEs were reported since 2021. We demonstrate that this therapeutic approach has merit, is durable, and should be explored in a larger clinical trial.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055968","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}
Yong Zhang, Xiang-Xiang Chen, Ruo Chen, Ling Li, Qing Ju, Dan Qiu, Yuan Wang, Peng-Yu Jing, Ning Chang, Min Wang, Jian Zhang, Zhi-Nan Chen, Ke Wang
<div> <section> <h3> Background</h3> <p>Gut microbiome on predicting clinical responses to immune checkpoint inhibitors (ICIs) has been discussed in detail for decades, while microecological features of the lower respiratory tract within advanced non-small-cell lung cancer (NSCLC) are still relatively vague.</p> </section> <section> <h3> Methods</h3> <p>During this study, 26 bronchoalveolar lavage fluids (BALF) from advanced NSCLC participants who received immune checkpoint inhibitor monotherapy were performed 16S rRNA sequencing and untargeted metabolome sequencing to identify differentially abundant microbes and metabolic characteristics. Additionally, inflammatory cytokines and chemokines were also launched in paired BALF and serum samples by immunoassays to uncover their underlying correlations. The omics data were separately analyzed and integrated by using multiple correlation coefficients. Multiplex immunohistochemical staining was then used to assess the immune cell infiltration after immune checkpoint blockade therapy.</p> </section> <section> <h3> Results</h3> <p>Lower respiratory tract microbiome diversity favoured preferred responses to ICIs. Microbial markers demonstrated microbial diversity overweight a single strain in favoured response to ICI therapy, where Bacillus matters. <i>Sphingomonas</i> and <i>Sediminibacterium</i> were liable to remodulate lipid and essential amino acid degradations to embrace progression after immunotherapies. Microbiome-derived metabolites reshaped the immune microenvironment in the lower respiratory tract by releasing inflammatory cytokines and chemokines, which was partially achieved by metabolite-mediated tumoral inflammatory products and reduction of CD8<sup>+</sup> effective T cells and M1 phenotypes macrophages in malignant lesions.</p> </section> <section> <h3> Conclusions</h3> <p>This study provided a microecological landscape of the lower respiratory tract with advanced NSCLC to ICI interventions and presented a multidimensional perspective with favoured outcomes that may improve the predictive capacity of the localized microbiome in clinical practices.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Alterations of the lower respiratory tract microbiome indicate different clinical responses to ICB within advanced NSCLC.</li> <li>Reduced microbial diversity of lower respiratory trac
{"title":"Lower respiratory tract microbiome dysbiosis impairs clinical responses to immune checkpoint blockade in advanced non-small-cell lung cancer","authors":"Yong Zhang, Xiang-Xiang Chen, Ruo Chen, Ling Li, Qing Ju, Dan Qiu, Yuan Wang, Peng-Yu Jing, Ning Chang, Min Wang, Jian Zhang, Zhi-Nan Chen, Ke Wang","doi":"10.1002/ctm2.70170","DOIUrl":"10.1002/ctm2.70170","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Gut microbiome on predicting clinical responses to immune checkpoint inhibitors (ICIs) has been discussed in detail for decades, while microecological features of the lower respiratory tract within advanced non-small-cell lung cancer (NSCLC) are still relatively vague.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>During this study, 26 bronchoalveolar lavage fluids (BALF) from advanced NSCLC participants who received immune checkpoint inhibitor monotherapy were performed 16S rRNA sequencing and untargeted metabolome sequencing to identify differentially abundant microbes and metabolic characteristics. Additionally, inflammatory cytokines and chemokines were also launched in paired BALF and serum samples by immunoassays to uncover their underlying correlations. The omics data were separately analyzed and integrated by using multiple correlation coefficients. Multiplex immunohistochemical staining was then used to assess the immune cell infiltration after immune checkpoint blockade therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Lower respiratory tract microbiome diversity favoured preferred responses to ICIs. Microbial markers demonstrated microbial diversity overweight a single strain in favoured response to ICI therapy, where Bacillus matters. <i>Sphingomonas</i> and <i>Sediminibacterium</i> were liable to remodulate lipid and essential amino acid degradations to embrace progression after immunotherapies. Microbiome-derived metabolites reshaped the immune microenvironment in the lower respiratory tract by releasing inflammatory cytokines and chemokines, which was partially achieved by metabolite-mediated tumoral inflammatory products and reduction of CD8<sup>+</sup> effective T cells and M1 phenotypes macrophages in malignant lesions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study provided a microecological landscape of the lower respiratory tract with advanced NSCLC to ICI interventions and presented a multidimensional perspective with favoured outcomes that may improve the predictive capacity of the localized microbiome in clinical practices.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Alterations of the lower respiratory tract microbiome indicate different clinical responses to ICB within advanced NSCLC.</li>\u0000 \u0000 <li>Reduced microbial diversity of lower respiratory trac","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964143","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}
{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70194","DOIUrl":"https://doi.org/10.1002/ctm2.70194","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143113748","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：