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Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis. 免疫治疗相关结肠炎患者肠道菌群的基线结肠炎原性和急性紊乱。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-12 DOI: 10.1084/jem.20232079
Joan Shang, Diane Marie Del Valle, Graham J Britton, K R Mead, Urvija Rajpal, Alice Chen-Liaw, Ilaria Mogno, Zhihua Li, Rajita Menon, Edgar Gonzalez-Kozlova, Arielle Elkrief, Jonathan U Peled, Tina Ruth Gonsalves, Neil J Shah, Michael Postow, Jean-Frederic Colombel, Sacha Gnjatic, David M Faleck, Jeremiah J Faith
{"title":"Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis.","authors":"Joan Shang, Diane Marie Del Valle, Graham J Britton, K R Mead, Urvija Rajpal, Alice Chen-Liaw, Ilaria Mogno, Zhihua Li, Rajita Menon, Edgar Gonzalez-Kozlova, Arielle Elkrief, Jonathan U Peled, Tina Ruth Gonsalves, Neil J Shah, Michael Postow, Jean-Frederic Colombel, Sacha Gnjatic, David M Faleck, Jeremiah J Faith","doi":"10.1084/jem.20232079","DOIUrl":"10.1084/jem.20232079","url":null,"abstract":"<p><p>Immunotherapy-related colitis (irC) frequently emerges as an immune-related adverse event during immune checkpoint inhibitor therapy and is presumably influenced by the gut microbiota. We longitudinally studied microbiomes from 38 ICI-treated cancer patients. We compared 13 ICI-treated subjects who developed irC against 25 ICI-treated subjects who remained irC-free, along with a validation cohort. Leveraging a preclinical mouse model, predisease stools from irC subjects induced greater colitigenicity upon transfer to mice. The microbiota during the first 10 days of irC closely resembled inflammatory bowel disease microbiomes, with reduced diversity, increased Proteobacteria and Veillonella, and decreased Faecalibacterium, which normalized before irC remission. These findings highlight the irC gut microbiota as functionally distinct but phylogenetically similar to non-irC and healthy microbiomes, with the exception of an acute, transient disruption early in irC. We underscore the significance of longitudinal microbiome profiling in developing clinical avenues to detect, monitor, and mitigate irC in ICI therapy cancer patients.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis. 靶向 CD206+ 巨噬细胞会破坏关键抗肿瘤免疫轴的建立。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-27 DOI: 10.1084/jem.20240957
Arja Ray, Kenneth H Hu, Kelly Kersten, Tristan Courau, Nicholas F Kuhn, Itzia Zaleta-Linares, Bushra Samad, Alexis J Combes, Matthew F Krummel
{"title":"Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis.","authors":"Arja Ray, Kenneth H Hu, Kelly Kersten, Tristan Courau, Nicholas F Kuhn, Itzia Zaleta-Linares, Bushra Samad, Alexis J Combes, Matthew F Krummel","doi":"10.1084/jem.20240957","DOIUrl":"10.1084/jem.20240957","url":null,"abstract":"<p><p>CD206 is a common marker of a putative immunosuppressive \"M2\" state in tumor-associated macrophages (TAMs). We made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs. Early depletion of CD206+ macrophages and monocytes (Mono/Macs) led to the indirect loss of conventional type I dendritic cells (cDC1), CD8 T cells, and NK cells in tumors. CD206+ TAMs robustly expressed CXCL9, contrasting with stress-responsive Spp1-expressing TAMs and immature monocytes, which became prominent with early depletion. CD206+ TAMs differentially attracted activated CD8 T cells, and the NK and CD8 T cells in CD206-depleted tumors were deficient in Cxcr3 and cDC1-supportive Xcl1 and Flt3l expressions. Disrupting this key antitumor axis decreased tumor control by antigen-specific T cells in mice. In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1, and NK signatures and was associated with better survival. These findings negate the unqualified classification of CD206+ \"M2-like\" macrophages as immunosuppressive.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142729266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis. STAG2-PAXIP1/PAGR1轴抑制肺肿瘤发生。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-09 DOI: 10.1084/jem.20240765
Emily L Ashkin, Yuning J Tang, Haiqing Xu, King L Hung, Julia A Belk, Hongchen Cai, Steven S Lopez, Deniz Nesli Dolcen, Jess D Hebert, Rui Li, Paloma A Ruiz, Tula Keal, Laura Andrejka, Howard Y Chang, Dmitri A Petrov, Jesse R Dixon, Zhichao Xu, Monte M Winslow
{"title":"A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis.","authors":"Emily L Ashkin, Yuning J Tang, Haiqing Xu, King L Hung, Julia A Belk, Hongchen Cai, Steven S Lopez, Deniz Nesli Dolcen, Jess D Hebert, Rui Li, Paloma A Ruiz, Tula Keal, Laura Andrejka, Howard Y Chang, Dmitri A Petrov, Jesse R Dixon, Zhichao Xu, Monte M Winslow","doi":"10.1084/jem.20240765","DOIUrl":"10.1084/jem.20240765","url":null,"abstract":"<p><p>The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and showed that STAG2 is uniquely tumor-suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. STAG2 inactivation elicits changes in gene expression, chromatin accessibility, and 3D genome conformation that impact the cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relate STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin-mediated mechanisms of lung tumor suppression.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Terez Shea-Donohue: Optimism helps, and confidence in your work is critical. 特雷兹-谢-多诺霍乐观会有帮助，对自己的工作充满信心至关重要。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-10-08 DOI: 10.1084/jem.20241693
Montserrat Cols
{"title":"Terez Shea-Donohue: Optimism helps, and confidence in your work is critical.","authors":"Montserrat Cols","doi":"10.1084/jem.20241693","DOIUrl":"10.1084/jem.20241693","url":null,"abstract":"<p><p>Terez Shea-Donohue is the program director of the Division of Digestive Diseases and Nutrition at the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. As a program director, Terez supports basic and translational research related to neurogastroenterology, gastrointestinal (GI), and GI epithelial barrier function. We spoke to Terez about the transition from active research to a predominantly administrative job, the need for life-long mentorship, and the continued sex/gender bias in health care.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Antiviral immunity lassoed down by excess RNA. 抗病毒免疫被过量的RNA束缚。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-06 DOI: 10.1084/jem.20241743
Erika Valeri, Anna Kajaste-Rudnitski
{"title":"Antiviral immunity lassoed down by excess RNA.","authors":"Erika Valeri, Anna Kajaste-Rudnitski","doi":"10.1084/jem.20241743","DOIUrl":"10.1084/jem.20241743","url":null,"abstract":"<p><p>Two complementary works by Chan et al. (https://doi.org/10.1084/jem.20231725), and Ru et al. (https://doi.org/10.1084/jem.20240010), identify defective RNA processing as the root cause of impaired antiviral immunity against SARS-CoV2 in the human brainstem. These studies provide molecular insight into virus-associated severe brainstem encephalitis through PKR inactivation.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer. 呼吸降低阻力：解决缺氧问题，克服肺癌免疫疗法障碍。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-25 DOI: 10.1084/jem.20241581
Huanhuan Joyce Chen
{"title":"Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer.","authors":"Huanhuan Joyce Chen","doi":"10.1084/jem.20241581","DOIUrl":"10.1084/jem.20241581","url":null,"abstract":"<p><p>In this issue of JEM, Robles-Oteiza et al. (https://doi.org/10.1084/jem.20231106) present compelling evidence linking tumor hypoxia to acquired resistance mechanisms in non-small cell lung cancer (NSCLC) treatments involving immune checkpoint inhibitors (ICIs). Their research advocates targeting these hypoxic tumor regions with hypoxia-activated pro-drugs like TH-302, which may substantially delay the onset of resistance and herald a significant advancement in cancer therapy.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile. 产生琥珀酸的微生物群促使簇细胞增生以抵御艰难梭菌。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-26 DOI: 10.1084/jem.20232055
Tasia D Kellogg, Simona Ceglia, Benedikt M Mortzfeld, Tanvi M Tanna, Abigail L Zeamer, Matthew R Mancini, Sage E Foley, Doyle V Ward, Shakti K Bhattarai, Beth A McCormick, Andrea Reboldi, Vanni Bucci
{"title":"Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile.","authors":"Tasia D Kellogg, Simona Ceglia, Benedikt M Mortzfeld, Tanvi M Tanna, Abigail L Zeamer, Matthew R Mancini, Sage E Foley, Doyle V Ward, Shakti K Bhattarai, Beth A McCormick, Andrea Reboldi, Vanni Bucci","doi":"10.1084/jem.20232055","DOIUrl":"10.1084/jem.20232055","url":null,"abstract":"<p><p>The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum. We demonstrate the causal role of the microbiome in modulating this phenotype using fecal matter transplantation and administration of consortia of succinate-producing bacteria. Administration of succinate production-deficient microbes shows a reduced response in a Pou2f3-dependent manner despite similar intestinal colonization. Finally, antibiotic-treated mice prophylactically administered with succinate-producing bacteria show increased protection against C. difficile-induced morbidity and mortality. This effect is nullified in Pou2f3-/- mice, confirming that the protection occurs via the TC pathway. We propose that activation of TCs by the microbiota in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by pathogens.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
MAIT cells: Conserved watchers on the wall. MAIT 细胞：墙壁上的守望者
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-10-24 DOI: 10.1084/jem.20232298
Lilou Germain, Pablo Veloso, Olivier Lantz, François Legoux
{"title":"MAIT cells: Conserved watchers on the wall.","authors":"Lilou Germain, Pablo Veloso, Olivier Lantz, François Legoux","doi":"10.1084/jem.20232298","DOIUrl":"10.1084/jem.20232298","url":null,"abstract":"<p><p>MAIT cells are innate-like T cells residing in barrier tissues such as the lung, skin, and intestine. Both the semi-invariant T cell receptor of MAIT cells and the restricting element MR1 are deeply conserved across mammals, indicating non-redundant functions linked to antigenic specificity. MAIT cells across species concomitantly express cytotoxicity and tissue-repair genes, suggesting versatile functions. Accordingly, MAIT cells contribute to antibacterial responses as well as to the repair of damaged barrier tissues. MAIT cells recognize riboflavin biosynthetic pathway-derived metabolites, which rapidly cross epithelial barriers to be presented by antigen-presenting cells. Changes in gut ecology during intestinal inflammation drive the expansion of strong riboflavin and MAIT ligand producers. Thus, MAIT cells may enable real-time surveillance of microbiota dysbiosis across intact epithelia and provide rapid and context-dependent responses. Here, we discuss recent findings regarding the origin and regulation of MAIT ligands and the role of MAIT cells in barrier tissues. We speculate on the potential reasons for MAIT cell conservation during evolution.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142501659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bridging the gap between tumor and disease: Innovating cancer and glioma models. 弥合肿瘤和疾病之间的鸿沟：创新癌症和胶质瘤模型。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-03 DOI: 10.1084/jem.20220808
Stefano M Cirigliano, Howard A Fine
{"title":"Bridging the gap between tumor and disease: Innovating cancer and glioma models.","authors":"Stefano M Cirigliano, Howard A Fine","doi":"10.1084/jem.20220808","DOIUrl":"10.1084/jem.20220808","url":null,"abstract":"<p><p>Recent advances in cancer biology and therapeutics have underscored the importance of preclinical models in understanding and treating cancer. Nevertheless, current models often fail to capture the complexity and patient-specific nature of human tumors, particularly gliomas. This review examines the strengths and weaknesses of such models, highlighting the need for a new generation of models. Emphasizing the critical role of the tumor microenvironment, tumor, and patient heterogeneity, we propose integrating our advanced understanding of glioma biology with innovative bioengineering and AI technologies to create more clinically relevant, patient-specific models. These innovations are essential for improving therapeutic development and patient outcomes.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11614461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An unconventional purine connection. 非传统的嘌呤联系
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-12-02 Epub Date: 2024-11-19 DOI: 10.1084/jem.20241527
Fabio Grassi
{"title":"An unconventional purine connection.","authors":"Fabio Grassi","doi":"10.1084/jem.20241527","DOIUrl":"10.1084/jem.20241527","url":null,"abstract":"<p><p>Xu et al. (https://doi.org/10.1084/jem.20240354) define NAD-induced cell death via purinergic P2RX7 receptor in type 1 unconventional T cells, particularly intrahepatic MAIT cells that are pivotal in liver homeostasis. Therefore, P2RX7 is a potential target to modulate unconventional T cells in immunopathological conditions and cancer.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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