Gut最新文献

{"title":"Spatial dissection of tumour microenvironments in gastric cancers reveals the immunosuppressive crosstalk between CCL2+ fibroblasts and STAT3-activated macrophages","authors":"Sung Hak Lee, Dagyeong Lee, Junyong Choi, Hye Jeong Oh, In-Hye Ham, Daeun Ryu, Seo-Yeong Lee, Dong-Jin Han, Sunmin Kim, Youngbeen Moon, In-Hye Song, Kyo Young Song, Hyeseong Lee, Seungho Lee, Hoon Hur, Tae-Min Kim","doi":"10.1136/gutjnl-2024-332901","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332901","url":null,"abstract":"Background A spatially resolved, niche-level analysis of tumour microenvironments (TME) can provide insights into cellular interactions and their functional impacts in gastric cancers (GC). Objective Our goal was to translate the spatial organisation of GC ecosystems into a functional landscape of cellular interactions involving malignant, stromal and immune cells. Design We performed spatial transcriptomics on nine primary GC samples using the Visium platform to delineate the transcriptional landscape and dynamics of malignant, stromal and immune cells within the GC tissue architecture, highlighting cellular crosstalks and their functional consequences in the TME. Results GC spatial transcriptomes with substantial cellular heterogeneity were delineated into six regional compartments. Specifically, the fibroblast-enriched TME upregulates epithelial-to-mesenchymal transformation and immunosuppressive response in malignant and TME cells, respectively. Cell type-specific transcriptional dynamics revealed that malignant and endothelial cells promote the cellular proliferations of TME cells, whereas the fibroblasts and immune cells are associated with procancer and anticancer immunity, respectively. Ligand-receptor analysis revealed that CCL2 -expressing fibroblasts promote the tumour progression via JAK-STAT3 signalling and inflammatory response in tumour-infiltrated macrophages. CCL2+ fibroblasts and STAT3 -activated macrophages are co-localised and their co-abundance was associated with unfavourable prognosis. We experimentally validated that CCL2+ fibroblasts recruit myeloid cells and stimulate STAT3 activation in recruited macrophages. The development of immunosuppressive TME by CCL2+ fibroblasts were also validated in syngeneic mouse models. Conclusion GC spatial transcriptomes revealed functional cellular crosstalk involving multiple cell types among which the interaction between CCL2+ fibroblasts and STAT3 -activated macrophages plays roles in establishing immune-suppressive GC TME with potential clinical relevance. Data are available in a public, open access repository. The datasets analysed in the current study are available in the TCGA Research Network (<https://www.cancer.gov/tcga>) and Gene Expression Omnibus (GEO) with accession ID GSE62254, GSE13861, GSE268999, GSE26901 and GSE28541. The sequencing data have been uploaded to GEO with accession ID GSE251950.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"24 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694149","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":"Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates.","authors":"Karol M Córdoba, Daniel Jericó, Lei Jiang, María Collantes, Manuel Alegre, Leyre García-Ruiz, Oscar Manzanilla, Ana Sampedro, Jose M Herranz, Iñigo Insausti, Antonio Martinez de la Cuesta, Francesco Urigo, Patricia Alcaide, María Morán, Miguel A Martín, José Luis Lanciego, Thibaud Lefebvre, Laurent Gouya, Gemma Quincoces, Carmen Unzu, Sandra Hervas-Stubbs, Juan M Falcón-Pérez, Estíbaliz Alegre, Azucena Aldaz, María A Fernández-Seara, Iván Peñuelas, Pedro Berraondo, Paolo G V Martini, Matias A Avila, Antonio Fontanellas","doi":"10.1136/gutjnl-2024-332619","DOIUrl":"10.1136/gutjnl-2024-332619","url":null,"abstract":"<p><strong>Objective: </strong>Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors.</p><p><strong>Design: </strong>We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic <i>PBGD</i> gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue.</p><p><strong>Results: </strong>Intrahepatic administration of a recombinant adeno-associated viral vector containing short hairpin RNA against endogenous PBGD mRNA resulted in sustained PBGD activity inhibition in liver tissue for up to 7 months postinjection. The administration of porphyrinogenic drugs to NHPs induced hepatic heme synthesis, elevated urinary porphyrin precursors and reproduced acute attack symptoms in patients with AIP, including pain, motor disturbances and increased brain GABAergic activity. The model also recapitulated functional anomalies associated with AIP, such as reduced brain perfusion and cerebral glucose uptake, disturbances in hepatic TCA cycle, one-carbon metabolism, drug biotransformation, lipidomic profile and abnormal mitochondrial respiratory chain activity. Additionally, repeated systemic administrations of hPBGD mRNA in this AIP NHP model restored hepatic PBGD levels and activity, providing successful protection against acute attacks, metabolic changes in the liver and CNS disturbances. This approach demonstrated better efficacy than the current standards of care for AIP.</p><p><strong>Conclusion: </strong>This novel model significantly expands our understanding of AIP at the molecular, biochemical and clinical levels and confirms the safety and translatability of multiple systemic administration of hPBGD mRNA as a potential aetiological AIP treatment.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375288","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":"Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression","authors":"Sarah S K Yue, Yin Tong, Hoi Cheong Siu, Siu Lun Ho, Simon Y K Law, Wai Yin Tsui, Dessy Chan, Yuanhua Huang, Annie S Y Chan, Shui Wa Yun, Ho Sang Hui, Jee-Eun Choi, Matthew S S Hsu, Frank P L Lai, April S Chan, Siu Tsan Yuen, Hans Clevers, Suet Yi Leung, Helen H N Yan","doi":"10.1136/gutjnl-2024-332594","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332594","url":null,"abstract":"Background Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models. Objective We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum. Design A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterisation were performed. Results Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates and reactivation of a fetal gene programme. Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain and epigenetic deregulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer. Conclusions Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention. Data are available in a public, open access repository. The WES, RNAseq, scRNAseq and scCNV data were deposited into the European Genome-Phenome Archive (EGAS00001007899). RNAseq, scRNAseq and methylation data were deposited to GEO, GSE210995.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"73 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678601","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":"Faecal phageome transplantation alleviates intermittent intestinal inflammation in IBD and the timing of transplantation matters: a preclinical proof-of-concept study in mice","authors":"Nengneng Li, Yue Li, Ziyu Huang, Zhirui Cao, Cha Cao, Xiang Gao, Tao Zuo","doi":"10.1136/gutjnl-2024-333598","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333598","url":null,"abstract":"We read with interest the Rome Consensus paper on faecal microbiota transplantation (FMT) in IBD (a refractory disease with intermittent flare-ups and remissions of intestinal inflammation) by Lopetuso et al .1 It highlights modest efficacies of FMT in treating IBD and adverse event risks caused by bacteria transplantation, according to data from clinical trials.1 Hence, further refinement of FMT is warranted for IBD treatment.2 3 Our prior study found that FMT can simultaneously reconfigure the gut bacteriome and phageome in patients with Clostridioides difficile infection; however, the reconfiguration of phageome was associated more with a long-term intestinal inflammation amelioration, suggesting a prominent role for gut bacteriophages in combating intestinal pathologies.4–6 Our more recent studies discovered a critically perturbed gut phageome in the intestinal mucosa of patients with IBD.7 8 Surprisingly, the distortion in the phageome-bacteriome ecology was even more pronounced in patients in remission compared with those in flare-up, implying the perturbed mucosal phageome during remission might be ‘quiescently’ fuelling disease flare-up.7 These findings together led us to hypothesise that targeting the perturbed gut phageome by faecal phageome transplantation (FPT), during the remission phase rather than the flare-up phase, might be a viable strategy for treating IBD. Inspired by this hypothesis, we conducted a preclinical proof-of-concept study in an IBD mouse model with intermittent, step-up dextran sulfate sodium (DSS) challenges (to mimic the relapsing and remitting disease courses of IBD), whereby we transplanted healthy faecal phageome at different intervention timings on the first round of DSS challenge (FPT administered during remission (FPT-r) vs flare-up (FPT-f)) and then evaluated treatment …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"19 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673281","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":"Identifying colorectal cancer-specific vulnerabilities in the Wnt-driven long non-coding transcriptome","authors":"Laura J Schwarzmueller, Ronja S Adam, Leandro F Moreno, Lisanne E Nijman, Adrian Logiantara, Steven Eleonora, Oscar Bril, Sophie Vromans, Nina E de Groot, Francesca Paola Giugliano, Ekaterina Stepanova, Vanesa Muncan, Clara C Elbers, Kristiaan J Lenos, Danny A Zwijnenburg, Monique A J van Eijndhoven, Dirk Michiel Pegtel, Sanne M van Neerven, Fabricio Loayza-Puch, Tulin Dadali, Wendy J Broom, Martin A Maier, Jan Koster, Louis Vermeulen, Nicolas Léveillé","doi":"10.1136/gutjnl-2024-332752","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332752","url":null,"abstract":"Background Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved. Objective In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets. Design We used global run-on sequencing to define β-catenin-regulated long non-coding RNAs (lncRNAs) in CRC. CRISPRi dropout screens were subsequently used to establish the functional relevance of a subset of these lncRNAs for long-term expansion of CRC. Results We uncovered that LINC02418 is essential for cancer cell clonogenic outgrowth. Mechanistically, LINC02418 regulates MYC expression levels to promote CRC stem cell functionality and prevent terminal differentiation. Furthermore, we developed effective small interfering RNA (siRNA)-based therapeutics to target LINC02418 RNA in vivo . Conclusion We propose that cancer-specific Wnt-regulated lncRNAs provide novel therapeutic opportunities to interfere with the Wnt pathway, which has so far defied effective pharmacological inhibition. Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. The sequence libraries generated in this study are publicly available through the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) under accession code: GSE206582.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"22 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673282","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":"Liquid biopsy to identify Barrett’s oesophagus, dysplasia and oesophageal adenocarcinoma: the EMERALD multicentre study","authors":"Jinsei Miyoshi, Alessandro Mannucci, Marco Scarpa, Feng Gao, Shusuke Toden, Timothy Whitsett, Landon J Inge, Ross M Bremner, Tetsuji Takayama, Yulan Cheng, Teodoro Bottiglieri, Iris D Nagetaal, Martha J Shrubsole, Ali H Zaidi, Xin Wang, Helen G Coleman, Lesley A Anderson, Stephen J Meltzer, Ajay Goel","doi":"10.1136/gutjnl-2024-333364","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333364","url":null,"abstract":"Background There is no clinically relevant serological marker for the early detection of oesophageal adenocarcinoma (EAC) and its precursor lesion, Barrett’s oesophagus (BE). Objective To develop and test a blood-based assay for EAC and BE. Design Oesophageal MicroRNAs of BaRRett, Adenocarcinoma and Dysplasia ( EMERALD ) was a large, international, multicentre biomarker cohort study involving 792 patient samples from 4 countries ([NCT06381583][1]) to develop and validate a circulating miRNA signature for the early detection of EAC and high-risk BE. Tissue-based miRNA sequencing and microarray datasets (n=134) were used to identify candidate miRNAs of diagnostic potential, followed by validation using 42 pairs of matched cancer and normal tissues. The usefulness of the candidate miRNAs was initially assessed using 108 sera (44 EAC, 34 EAC precursors and 30 non-disease controls). We finally trained a machine learning model (XGBoost+AdaBoost) on RT-qPCR results from circulating miRNAs from a training cohort (n=160) and independently tested it in an external cohort (n=295). Results After a strict process of biomarker discovery and selection, we identified six miRNAs that were overexpressed in all sera of patients compared with non-disease controls from three independent cohorts of different nationalities (miR-106b, miR-146a, miR-15a, miR-18a, miR-21 and miR-93). We established a six-miRNA diagnostic signature using the training cohort (area under the receiver operating characteristic curve (AUROC): 97.6%) and tested it in an independent cohort (AUROC: 91.9%). This assay could also identify patients with BE among patients with gastro-oesophageal reflux disease (AUROC: 94.8%, sensitivity: 92.8%, specificity: 85.1%). Conclusion Using a comprehensive approach integrating unbiased genome-wide biomarker discovery and several independent experimental validations, we have developed and validated a novel blood test that might complement screening options for BE/EAC. Trial registration number [NCT06381583][1]. Data sharing not applicable as no datasets generated and/or analysed for this study. Data collected for the study, including deidentified participant data and the code, will be made available to others at publication via a signed data access agreement and at the discretion of the investigators’ approval of the proposed use of such data. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT06381583&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F18%2Fgutjnl-2024-333364.atom","PeriodicalId":12825,"journal":{"name":"Gut","volume":"230 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673284","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":"Devices substitution can reduce environmental burden: what about strategies substitution?","authors":"Raphaëlle Grau, Jérémie Jacques, Jérôme Rivory, Mathieu Pioche","doi":"10.1136/gutjnl-2024-334092","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334092","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638666","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":"Recent advances in clinical practice: mastering the challenge—managing IBS symptoms in IBD","authors":"Judith Wellens, João Sabino, Tim Vanuytsel, Jan Tack, Séverine Vermeire","doi":"10.1136/gutjnl-2024-333565","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333565","url":null,"abstract":"Many patients with IBD report persisting symptoms, despite resolution of the inflammatory process. Although by definition, a diagnosis of IBS cannot be made, the prevalence of ‘IBS in IBD’ surpasses the rate of IBS in the global population by fivefold. Because IBS-like symptoms are associated with a decreased quality of life and increased healthcare utilisation in IBD, diagnosis and treatment are necessary. In this review, we summarise the current knowledge on IBS-like symptoms in IBD. A pathophysiological common ground is present, which includes genetic susceptibility, environmental triggers, gut microbial dysbiosis, increased intestinal permeability, visceral hypersensitivity and involvement of brain–gut interaction. When symptoms persist after resolution of inflammation, other GI diseases should be excluded based on the chief complaint, considering any possible psychological co-morbidity early in the diagnostic work-up. Subsequent treatment should be initiated that is evidence-based and often multimodal, including classical and non-classical pharmacological agents as well as lifestyle and microbiota-based approaches, spanning the breadth of the gut, brain and its interaction. Treatment goals in this substantial part of the IBD population should be adapted to not only focus on treating the inflammation but taking care of the patient.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"10 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601016","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":"Large proximal gastric GIST tumours: downsizing by imatinib and subsequent endoresection","authors":"Ayimukedisi Yalikong, Baohui Song, Dongli He, Enpan Xu, Zhipeng Qi, Yunshi Zhong","doi":"10.1136/gutjnl-2024-332993","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332993","url":null,"abstract":"Surgical removal is recommended for gastrointestinal stromal tumours (GISTs) larger than 3 cm due to their potential for malignancy but limited wedge resection is not possible in the proximal stomach. Endoscopic removal of larger lesions has been technically limited in complex anatomical regions such as cardia. We report two cases of large proximal (cardia/fundus) GIST tumours (51 and 60 mm) which were downsized (to 26 and 36 mm) by 3–7 months of imatinib therapy followed by transmural endoscopic resection. Follow-up of 23 and 16 months including endoscopy and CT was unremarkable. GISTs commonly occur in the stomach.1 2 Due to their malignant potential, surgery is generally recommended.3–5 Recently, endoscopic resection of submucosal tumours (SMTs) has made significant progress.6 The European Society of Gastrointestinal Endoscopy recommended endoscopic resection for gastric GISTs<35 mm projecting into the lumen.3 Endoscopic full-thickness resection (EFTR), an extension of submucosal dissection, has shown promising results for SMTs arising from the deep muscularis propria (MP), particularly in the gastric fundus.7 However, achieving R0 resection in GISTs>35 mm remains challenging.8 Large GISTs in anatomically complex areas such as the cardia and fundus may still necessitate surgical resection.2 Radical surgery, however, poses risks to cardia function and patient quality of life.9 Preoperative imatinib can shrink tumours, reduce mitotic activity and lower recurrence risk.9 10 The American College of Gastroenterology guidelines suggested neoadjuvant imatinib to facilitate tumour reduction in large GISTs, enhancing the feasibility of minimally invasive endoscopic resection. Hence, in this context, we explored the combination of preoperative imatinib with EFTR as a novel, minimally invasive strategy for treating large gastric GISTs. Our primary outcomes suggested this approach may be a viable alternative for GISTs in gastric anatomical complex regions. Case 1 was a 65-year-old woman with abdominal distension and belching for several months. Gastroscopy revealed …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"159 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601017","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":"CAF-macrophage crosstalk in tumour microenvironments governs the response to immune checkpoint blockade in gastric cancer peritoneal metastases","authors":"Yuanfang Li, Yongqiang Zheng, Jiaqian Huang, Run-Cong Nie, Qi-Nian Wu, Zhijun Zuo, Shuqiang Yuan, Kai Yu, Cheng-Cai Liang, Yi-Qian Pan, Bai-Wei Zhao, Yuhong Xu, Qihua Zhang, Yashang Zheng, Junquan Chen, Zhao-Lei Zeng, Wei Wei, Ze-Xian Liu, Rui-Hua Xu, Hui-Yan Luo","doi":"10.1136/gutjnl-2024-333617","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333617","url":null,"abstract":"Background Peritoneal metastasis is the most common metastasis pattern of gastric cancer. Patients with gastric cancer peritoneal metastasis (GCPM) have a poor prognosis and respond poorly to conventional treatments. Recently, immune checkpoint blockade (ICB) has demonstrated favourable efficacy in the treatment of GCPM. Stratification of best responders and elucidation of resistance mechanisms of ICB therapies are highly important and remain major clinical challenges. Design We performed a phase II trial involving patients with GCPM treated with ICB (sintilimab) combined with chemotherapy. The samples of primary tumours, GCPMs and peripheral blood from patients were collected for single-cell sequencing to comprehensively interpret the tumour microenvironment of GCPM and its impacts on immunotherapy efficacy. Results The GCPM ecosystem coordinates a unique immunosuppressive pattern distinct from that of primary GC, which is dominated by a stroma-myeloid niche composed of SPP1+tumour-associated macrophages (TAMs) and Thrombospondin 2 (THBS2)+matrix cancer-associated fibroblasts (mCAFs). Consequently, this stroma-myeloid crosstalk is the major mediator of ICB resistance in patients with GCPM. Mechanistically, the accumulated THBS2+mCAFs facilitate the recruitment of peritoneum-specific tissue-resident macrophages and their transformation into SPP1+TAMs via the complement C3 and its receptor C3a receptor 1 (C3AR1), thereby forming a protumoral stroma-myeloid niche. Blocking the C3-C3AR1 axis disrupts the stroma-myeloid crosstalk and thereby significantly improves the benefits of ICB in in vivo models. Conclusion Our findings provide a new molecular portrait of cell compositions associated with ICB resistance in patients with GCPM and aid in the prioritisation of therapeutic candidates to potentiate immunotherapy. Data are available in a public, open access repository. Data are available on reasonable request. The sample information is listed in online supplemental table S1. The 10X genomics raw data of this study are deposited in the Genome Sequence Archive for Human database (ID: HRA009064; link: [https://ngdc.cncb.ac.cn/gsa-human/browse/HRA009064][1]). Additionally, the GEXSCOPE single-cell matrix data are deposited in the Mendeley repository (ID: jwkc5t6r55). Previously published scRNA-seq data that were reanalysed and integrated into this study are available in the Gene Expression Omnibus database under accession code GSE183904. All the data that support the findings of this study are available from the corresponding author on reasonable request. [1]: https://ngdc.cncb.ac.cn/gsa-human/browse/HRA009064)","PeriodicalId":12825,"journal":{"name":"Gut","volume":"196 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601015","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}