Immature innate and adaptive immunity and vulnerability of narrower airways to obstruction increase the susceptibility of infants to severe respiratory syncytial virus (RSV) disease. In this issue of the JCI, Zhao et al. illustrated greater intrinsic susceptibility of pediatric versus adult airway epithelial cells to RSV-induced cytopathology. Using precision cut lung slices (PCLS) and air-liquid interface (ALI) airway epithelial cell cultures, the authors showed that impaired STAT3 activation in RSV-infected pediatric multiciliated cells increased cell apoptosis and viral shedding, which enhanced the spread of infection. Bolstering STAT3 activation and treatment of neonatal mice with apoptosis inhibitors suppressed virus spread, suggesting that enhancing STAT3 activation may provide therapeutic benefit.
{"title":"Enhanced susceptibility of pediatric airway epithelium to respiratory syncytial virus infection.","authors":"Raymond J Pickles, Gang Chen, Scott H Randell","doi":"10.1172/JCI185689","DOIUrl":"10.1172/JCI185689","url":null,"abstract":"<p><p>Immature innate and adaptive immunity and vulnerability of narrower airways to obstruction increase the susceptibility of infants to severe respiratory syncytial virus (RSV) disease. In this issue of the JCI, Zhao et al. illustrated greater intrinsic susceptibility of pediatric versus adult airway epithelial cells to RSV-induced cytopathology. Using precision cut lung slices (PCLS) and air-liquid interface (ALI) airway epithelial cell cultures, the authors showed that impaired STAT3 activation in RSV-infected pediatric multiciliated cells increased cell apoptosis and viral shedding, which enhanced the spread of infection. Bolstering STAT3 activation and treatment of neonatal mice with apoptosis inhibitors suppressed virus spread, suggesting that enhancing STAT3 activation may provide therapeutic benefit.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557896","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}
Sarah Hamze Sinno, Joshua A Imperatore, Shoumei Bai, Noémie Gomes-Jourdan, Nyasha Mafarachisi, Claudia Coronnello, Linan Zhang, Eldin Jašarević, Hatice U Osmanbeyoglu, Ronald J Buckanovich, Sandra Cascio
Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cell migration and promotes their differentiation toward an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intratumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10, and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to anti-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of anti-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression colocalized with myeloid cell infiltration. scRNA-Seq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the oncoimmunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential therapeutic target to enhance immunotherapy in patients with OvCa.
{"title":"Egfl6 promotes ovarian cancer progression by enhancing the immunosuppressive functions of tumor-associated myeloid cells.","authors":"Sarah Hamze Sinno, Joshua A Imperatore, Shoumei Bai, Noémie Gomes-Jourdan, Nyasha Mafarachisi, Claudia Coronnello, Linan Zhang, Eldin Jašarević, Hatice U Osmanbeyoglu, Ronald J Buckanovich, Sandra Cascio","doi":"10.1172/JCI175147","DOIUrl":"10.1172/JCI175147","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cell migration and promotes their differentiation toward an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intratumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10, and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to anti-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of anti-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression colocalized with myeloid cell infiltration. scRNA-Seq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the oncoimmunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential therapeutic target to enhance immunotherapy in patients with OvCa.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307851","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}
Saptarshi Sinha, Brennan W Callow, Alex P Farfel, Suchismita Roy, Siyi Chen, Maria Masotti, Shrila Rajendran, Johanna M Buschhaus, Celia R Espinoza, Kathryn E Luker, Pradipta Ghosh, Gary D Luker
Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between 'borrowed' and 'intrinsic' components. Bioinformatics prioritized one of the 'borrowed' components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the 'borrowed' and the 'intrinsic' gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
{"title":"Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels.","authors":"Saptarshi Sinha, Brennan W Callow, Alex P Farfel, Suchismita Roy, Siyi Chen, Maria Masotti, Shrila Rajendran, Johanna M Buschhaus, Celia R Espinoza, Kathryn E Luker, Pradipta Ghosh, Gary D Luker","doi":"10.1172/JCI170953","DOIUrl":"10.1172/JCI170953","url":null,"abstract":"<p><p>Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between 'borrowed' and 'intrinsic' components. Bioinformatics prioritized one of the 'borrowed' components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the 'borrowed' and the 'intrinsic' gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557890","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}
Andrés R Muñoz-Rojas, Adam C Wang, Lisa E Pomeranz, Elizabeth L Reizis, Heather W Stout-Delgado, Ileana C Miranda, Krishnan Rajagopalan, Tadiwanashe Gwatiringa, Roger R Fan, Ahmad A Huda, Neha Maskey, Roseline P Olumuyide, Aryan S Patel, Jeffrey M Friedman, Diane Mathis, Kartik N Rajagopalan
{"title":"Leptin signaling maintains autonomic stability during severe influenza infection in mice.","authors":"Andrés R Muñoz-Rojas, Adam C Wang, Lisa E Pomeranz, Elizabeth L Reizis, Heather W Stout-Delgado, Ileana C Miranda, Krishnan Rajagopalan, Tadiwanashe Gwatiringa, Roger R Fan, Ahmad A Huda, Neha Maskey, Roseline P Olumuyide, Aryan S Patel, Jeffrey M Friedman, Diane Mathis, Kartik N Rajagopalan","doi":"10.1172/JCI182550","DOIUrl":"10.1172/JCI182550","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557892","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}
Zhenyan Jiang, Huizi Wang, Xiaoxia Wang, Hongrui Duo, Yuexiao Tao, Jia Li, Xin Li, Jiamin Liu, Jun Ni, Emily Jiatong Wu, Hongrui Xiang, Chenyang Guan, Xinyu Wang, Kun Zhang, Peng Zhang, Zhaoyuan Hou, Yong Liu, Zhengting Wang, Bing Su, Bo Li, Youjin Hao, Bin Li, Xuefeng Wu
Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining regulatory T cells (Treg) stability and function, yet the underlying mechanism remains largely unexplored. Here we demonstrate that ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) Treg-specific knockout (Tmed4ΔTreg) mice contain more Treg cells with impaired Foxp3 stability, Treg signature and suppressive activity, which leads to T cell hyperactivation, exacerbated inflammatory phenotype and boosted anti-tumor immunity in mice. Mechanistically, loss of Tmed4 causes defects in ERS and nuclear factor erythroid 2-related factor 2 (NRF2)-related antioxidant response, which results in excessive reactive oxygen species (ROS) that reduces Foxp3 stability and suppressive function of Treg cells in an IRE1α-XBP1 axis-dependent manner. The abnormalities can be effectively rescued by ROS scavenger, NRF2 inducer or forcible expression of IRE1α. Moreover, TMED4 suppresses IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including BIP. Our study reveals that TMED4 maintains Treg cell stability and suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.
内质网应激(ERS)在维持调节性 T 细胞(Treg)的稳定性和功能方面起着至关重要的作用,但其潜在机制在很大程度上仍未得到探索。在这里,我们证明了ERS相关蛋白跨膜p24转运蛋白4(TMED4)Treg特异性敲除(Tmed4ΔTreg)小鼠含有更多的Treg细胞,其Foxp3稳定性、Treg特征和抑制活性受损,从而导致小鼠T细胞过度活化、炎症表型恶化和抗肿瘤免疫力增强。从机理上讲,Tmed4的缺失会导致ERS和核因子红细胞2相关因子2(NRF2)相关的抗氧化反应缺陷,从而导致过量的活性氧(ROS),以IRE1α-XBP1轴依赖的方式降低Foxp3的稳定性和Treg细胞的抑制功能。ROS清除剂、NRF2诱导剂或IRE1α的强制表达可有效地挽救这些异常。此外,TMED4还能通过包括BIP在内的ER相关降解(ERAD)系统抑制IRE1α蛋白体降解。我们的研究揭示了TMED4通过IRE1α依赖的ROS和NRF2相关的抗氧化反应维持Treg细胞的稳定性和抑制功能。
{"title":"TMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models.","authors":"Zhenyan Jiang, Huizi Wang, Xiaoxia Wang, Hongrui Duo, Yuexiao Tao, Jia Li, Xin Li, Jiamin Liu, Jun Ni, Emily Jiatong Wu, Hongrui Xiang, Chenyang Guan, Xinyu Wang, Kun Zhang, Peng Zhang, Zhaoyuan Hou, Yong Liu, Zhengting Wang, Bing Su, Bo Li, Youjin Hao, Bin Li, Xuefeng Wu","doi":"10.1172/JCI179874","DOIUrl":"10.1172/JCI179874","url":null,"abstract":"<p><p>Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining regulatory T cells (Treg) stability and function, yet the underlying mechanism remains largely unexplored. Here we demonstrate that ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) Treg-specific knockout (Tmed4ΔTreg) mice contain more Treg cells with impaired Foxp3 stability, Treg signature and suppressive activity, which leads to T cell hyperactivation, exacerbated inflammatory phenotype and boosted anti-tumor immunity in mice. Mechanistically, loss of Tmed4 causes defects in ERS and nuclear factor erythroid 2-related factor 2 (NRF2)-related antioxidant response, which results in excessive reactive oxygen species (ROS) that reduces Foxp3 stability and suppressive function of Treg cells in an IRE1α-XBP1 axis-dependent manner. The abnormalities can be effectively rescued by ROS scavenger, NRF2 inducer or forcible expression of IRE1α. Moreover, TMED4 suppresses IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including BIP. Our study reveals that TMED4 maintains Treg cell stability and suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557893","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}
Myocardial infarction (MI) is characterized by massive cardiomyocytes death and cardiac dysfunction, and effective therapies to achieve cardioprotection are sorely needed. Here we reported that flavin containing monooxygenase 2 (FMO2) level was markedly increased in cardiomyocytes both in ex vivo and in vivo models of ischemia injury. Genetic deletion of FMO2 resulted in reduced cardiomyocyte survival and enhanced cardiac dysfunction, whereas cardiomyocyte-specific FMO2 overexpression exerted a protective effect in infarcted rat hearts. Mechanistically, FMO2 inhibited the activation of endoplasmic reticulum (ER) stress-induced apoptotic proteins, including caspase 12 and C/EBP homologous protein (CHOP), by down-regulating unfolded protein response (UPR) pathway. Furthermore, we identified FMO2 as a chaperone that catalyzed disulfide-bond formation in unfolded/misfolded proteins through its GVSG motif. GVSG-mutated FMO2 failed to catalyze disulfide-bond formation and lost its protection against ER stress and cardiomyocyte death. Finally, we demonstrated the protective effect of FMO2 in human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model. Collectively, this study highlights FMO2 as a key modulator of oxidative protein folding in cardiomyocytes and underscores its therapeutic potential for treating ischemic heart disease.
{"title":"Flavin-containing monooxygenase 2 confers cardioprotection in ischemia models through its disulfide-bond catalytic activity.","authors":"Qingnian Liu, Jiniu Huang, Hao Ding, Yue Tao, Jinliang Nan, Changchen Xiao, Yingchao Wang, Rongrong Wu, Cheng Ni, Zhiwei Zhong, Wei Zhu, Jinghai Chen, Chenyun Zhang, Xiao He, Danyang Xiong, Xinyang Hu, Jian'an Wang","doi":"10.1172/JCI177077","DOIUrl":"10.1172/JCI177077","url":null,"abstract":"<p><p>Myocardial infarction (MI) is characterized by massive cardiomyocytes death and cardiac dysfunction, and effective therapies to achieve cardioprotection are sorely needed. Here we reported that flavin containing monooxygenase 2 (FMO2) level was markedly increased in cardiomyocytes both in ex vivo and in vivo models of ischemia injury. Genetic deletion of FMO2 resulted in reduced cardiomyocyte survival and enhanced cardiac dysfunction, whereas cardiomyocyte-specific FMO2 overexpression exerted a protective effect in infarcted rat hearts. Mechanistically, FMO2 inhibited the activation of endoplasmic reticulum (ER) stress-induced apoptotic proteins, including caspase 12 and C/EBP homologous protein (CHOP), by down-regulating unfolded protein response (UPR) pathway. Furthermore, we identified FMO2 as a chaperone that catalyzed disulfide-bond formation in unfolded/misfolded proteins through its GVSG motif. GVSG-mutated FMO2 failed to catalyze disulfide-bond formation and lost its protection against ER stress and cardiomyocyte death. Finally, we demonstrated the protective effect of FMO2 in human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model. Collectively, this study highlights FMO2 as a key modulator of oxidative protein folding in cardiomyocytes and underscores its therapeutic potential for treating ischemic heart disease.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557891","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}
Brad H Nelson, Phineas T Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald Li Stevens, Shreena Kalaria, Karanvir Singh, Céline M Laumont, Elena Moss, Aliya Alimujiang, Nicola S Meagher, Adelyn Bolithon, Sian Fereday, Catherine J Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L Goode, Anthony N Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A Doherty, Holly R Harris, Kara L Cushing-Haugen, Michael S Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul Dp Pharoah, Jessica Boros, Alison H Brand, Paul R Harnett, Raghwa Sharma, Jonathan L Hecht, Naoko Sasamoto, Kathryn L Terry, Beth Y Karlan, Jenny Lester, Michael E Carney, Marc T Goodman, Brenda Y Hernandez, Lynne R Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A Fasching, Christiani Bisinotto, Francisco José Candido Dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S Cook, Nhu D Le, Aleksandra Gentry-Maharaj, Usha Menon, María J García, Cristina Rodriguez-Antona, Kyo M Farrington, Linda E Kelemen, Stefan Kommoss, Annette Staebler, Dale W Garsed, James D Brenton, Anna M Piskorz, David Dl Bowtell, Anna DeFazio, Susan J Ramus, Malcolm C Pike, Celeste Leigh Pearce
<p><strong>Background: </strong>Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment.</p><p><strong>Methods: </strong>We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.</p><p><strong>Results: </strong>Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.</p><p><strong>Conclusions: </strong>The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy.</p><p><strong>Funding: </strong>Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hosp
背景:尽管总体预后较差,但约有15%的晚期输卵管高分化浆液性癌(HGSC)患者在接受标准治疗后可存活十年以上:尽管总体预后不佳,但仍有约 15%的晚期输卵管卵巢高级别浆液性癌(HGSC)患者在接受标准治疗后存活 10 年或更长时间:我们利用一个大型国际队列对这一特殊且研究不足的群体的肿瘤微环境进行了评估,与中期(MTS;5-7.99 年;n = 433)和短期(STS;2-4.99 年;n = 416)幸存者相比,长期幸存者(LTS;10 年以上;n = 374)更多。对原发肿瘤样本进行免疫染色,并对10个免疫细胞亚群(包括T细胞、B细胞、浆细胞、髓样细胞、PD-1+细胞和PD-L1+细胞)的上皮内和基质内密度以及上皮含量进行评分:与 STS 相比,9/10 的免疫细胞亚群与 LTS 呈正相关。尤其是上皮内 CD8+ T 细胞和间质内 B 细胞的组合,与 STS 相比,LTS 的几率增加了近五倍。所有这些关联在上皮含量高和/或C4/分化分子亚型的肿瘤中更强,尽管免疫细胞密度在上皮含量低和/或C2/免疫反应分子亚型的肿瘤中通常更高:HGSC长期存活者的肿瘤微环境具有T细胞和B细胞共同浸润、上皮细胞含量高和C4/分化分子亚型等特征,这些特征可能为免疫疗法提供新的灵感:经费来源:美国国防部(DOD)国会指导医学研究计划(CDMRP)的卵巢癌研究计划(OCRP)。Andersen 基金会;Genome BC;德国癌症研究中心;德国联邦教育与研究部,临床生物医学研究计划;卡洛斯三世健康研究所;梅奥基金会;明尼苏达卵巢癌联盟;Ministerio de Economía y Competitividad;MRC;国家转化科学促进中心;澳大利亚国家健康与医学研究委员会 (NHMRC)、澳大利亚卵巢癌协会、Peter MacCallum 基金会、悉尼西部转化癌症研究中心、特里-福克斯研究所、夏娃呼吁(橡树基金会)、剑桥大学英国国家健康研究所生物医学研究中心、匹兹堡大学医学院、U.美国国立卫生研究院国家癌症研究所;VGH 和 UBC 医院基金会;维多利亚州癌症机构。
{"title":"Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.","authors":"Brad H Nelson, Phineas T Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald Li Stevens, Shreena Kalaria, Karanvir Singh, Céline M Laumont, Elena Moss, Aliya Alimujiang, Nicola S Meagher, Adelyn Bolithon, Sian Fereday, Catherine J Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L Goode, Anthony N Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A Doherty, Holly R Harris, Kara L Cushing-Haugen, Michael S Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul Dp Pharoah, Jessica Boros, Alison H Brand, Paul R Harnett, Raghwa Sharma, Jonathan L Hecht, Naoko Sasamoto, Kathryn L Terry, Beth Y Karlan, Jenny Lester, Michael E Carney, Marc T Goodman, Brenda Y Hernandez, Lynne R Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A Fasching, Christiani Bisinotto, Francisco José Candido Dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S Cook, Nhu D Le, Aleksandra Gentry-Maharaj, Usha Menon, María J García, Cristina Rodriguez-Antona, Kyo M Farrington, Linda E Kelemen, Stefan Kommoss, Annette Staebler, Dale W Garsed, James D Brenton, Anna M Piskorz, David Dl Bowtell, Anna DeFazio, Susan J Ramus, Malcolm C Pike, Celeste Leigh Pearce","doi":"10.1172/JCI179501","DOIUrl":"https://doi.org/10.1172/JCI179501","url":null,"abstract":"<p><strong>Background: </strong>Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment.</p><p><strong>Methods: </strong>We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.</p><p><strong>Results: </strong>Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.</p><p><strong>Conclusions: </strong>The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy.</p><p><strong>Funding: </strong>Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hosp","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545751","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}
Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster
mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated the effects of reinforcing costimulation via 4-1BB, a member of the TNF receptor superfamily, on immune responses elicited by mRNA vaccines. We first immunized mice with mRNA vaccines, followed by treatment with 4-1BB costimulatory antibodies to reinforce the 4-1BB pathway at different timepoints post-vaccination. Consistent with prior studies, reinforcing 4-1BB costimulation on the day of vaccination did not result in a substantial improvement of vaccine responses. However, reinforcing 4-1BB costimulation at day 4 post-vaccination, when 4-1BB expression levels were highest, resulted in a profound improvement of CD8 T cell responses associated with enhanced protection against pathogen challenges. A similar clinical benefit was observed in a therapeutic cancer vaccine model. We also report time-dependent effects with OX40, another costimulatory molecule of the TNF receptor superfamily. These findings demonstrate that delayed reinforcement of costimulation may exert an immunologic benefit, providing insights for the development of more effective mRNA vaccines for infectious diseases and cancer.
{"title":"Delayed reinforcement of costimulation improves the efficacy of mRNA vaccines in mice.","authors":"Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster","doi":"10.1172/JCI183973","DOIUrl":"10.1172/JCI183973","url":null,"abstract":"<p><p>mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated the effects of reinforcing costimulation via 4-1BB, a member of the TNF receptor superfamily, on immune responses elicited by mRNA vaccines. We first immunized mice with mRNA vaccines, followed by treatment with 4-1BB costimulatory antibodies to reinforce the 4-1BB pathway at different timepoints post-vaccination. Consistent with prior studies, reinforcing 4-1BB costimulation on the day of vaccination did not result in a substantial improvement of vaccine responses. However, reinforcing 4-1BB costimulation at day 4 post-vaccination, when 4-1BB expression levels were highest, resulted in a profound improvement of CD8 T cell responses associated with enhanced protection against pathogen challenges. A similar clinical benefit was observed in a therapeutic cancer vaccine model. We also report time-dependent effects with OX40, another costimulatory molecule of the TNF receptor superfamily. These findings demonstrate that delayed reinforcement of costimulation may exert an immunologic benefit, providing insights for the development of more effective mRNA vaccines for infectious diseases and cancer.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466685","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}
Expression of tissue-restricted antigens (TRAs) within the thymus is critical for the establishment of self-tolerance; however, exact mechanisms regulating the expression of TRAs has proven more complex than previously appreciated. In this issue of the JCI, Muro et al. identify a central role for protein arginine methyltransferase 5 (PRMT5) in posttranscriptional regulation of TRAs and thereby central tolerance. Using conditional KO mice, the authors showed that thymic deficiency of Prmt5 predisposed mice to developing autoimmune diseases while enhancing antitumor efficacy. These studies provide insight into the role of PRMT5 in shaping the T cell repertoire with implications for the development of therapies.
胸腺内组织限制性抗原(TRAs)的表达对自我耐受的建立至关重要;然而,事实证明,TRAs 表达的确切调控机制比以前所认识到的要复杂得多。在本期 JCI 杂志上,Muro 等人发现了蛋白精氨酸甲基转移酶 5 (PRMT5) 在转录后调控 TRAs 以及中枢耐受中的核心作用。作者利用条件性 KO 小鼠表明,胸腺缺乏 Prmt5 会使小鼠易患自身免疫性疾病,同时提高抗肿瘤效果。这些研究深入揭示了 PRMT5 在形成 T 细胞库中的作用,对开发疗法具有重要意义。
{"title":"PRMT5: splicing up tolerance.","authors":"Rathan Kumar, Parvathi Ranganathan","doi":"10.1172/JCI185701","DOIUrl":"https://doi.org/10.1172/JCI185701","url":null,"abstract":"<p><p>Expression of tissue-restricted antigens (TRAs) within the thymus is critical for the establishment of self-tolerance; however, exact mechanisms regulating the expression of TRAs has proven more complex than previously appreciated. In this issue of the JCI, Muro et al. identify a central role for protein arginine methyltransferase 5 (PRMT5) in posttranscriptional regulation of TRAs and thereby central tolerance. Using conditional KO mice, the authors showed that thymic deficiency of Prmt5 predisposed mice to developing autoimmune diseases while enhancing antitumor efficacy. These studies provide insight into the role of PRMT5 in shaping the T cell repertoire with implications for the development of therapies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 20","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466687","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}
Andrew P Hederman, Christopher Al Remmel, Shilpee Sharma, Harini Natarajan, Joshua A Weiner, Daniel Wrapp, Catherine Donner, Marie-Luce Delforge, Piera d'Angelo, Milena Furione, Chiara Fornara, Jason S McLellan, Daniele Lilleri, Arnaud Marchant, Margaret E Ackerman
BACKGROUNDMost humans have been infected with cytomegalovirus (CMV) by midlife without clinical signs of disease. However, in settings in which the immune system is undeveloped or compromised, the virus is not adequately controlled and consequently presents a major infectious cause of both congenital disease during pregnancy as well as opportunistic infection in children and adults. With clear evidence that risk to the fetus varies with gestational age at the time of primary maternal infection, further research on humoral responses to primary CMV infection during pregnancy is needed.METHODSHere, systems serology tools were applied to characterize antibody responses to CMV infection in pregnant and nonpregnant women experiencing either primary or chronic infection.RESULTSWhereas strikingly different antibody profiles were observed depending on infection status, limited differences were associated with pregnancy status. Beyond known differences in IgM responses used clinically for identification of primary infection, distinctions observed in IgA and FcγR-binding antibodies and among antigen specificities accurately predicted infection status. Machine learning was used to define the transition from primary to chronic states and predict time since infection with high accuracy. Humoral responses diverged over time in an antigen-specific manner, with IgG3 responses toward tegument decreasing over time as typical of viral infections, while those directed to pentamer and glycoprotein B were lower during acute and greatest during chronic infection.CONCLUSIONIn sum, this work provides insights into the antibody response associated with CMV infection status in the context of pregnancy, revealing aspects of humoral immunity that have the potential to improve CMV diagnostics.FUNDINGCYMAF consortium and NIH NIAID.
{"title":"Discrimination of primary and chronic cytomegalovirus infection based on humoral immune profiles in pregnancy.","authors":"Andrew P Hederman, Christopher Al Remmel, Shilpee Sharma, Harini Natarajan, Joshua A Weiner, Daniel Wrapp, Catherine Donner, Marie-Luce Delforge, Piera d'Angelo, Milena Furione, Chiara Fornara, Jason S McLellan, Daniele Lilleri, Arnaud Marchant, Margaret E Ackerman","doi":"10.1172/JCI180560","DOIUrl":"10.1172/JCI180560","url":null,"abstract":"<p><p>BACKGROUNDMost humans have been infected with cytomegalovirus (CMV) by midlife without clinical signs of disease. However, in settings in which the immune system is undeveloped or compromised, the virus is not adequately controlled and consequently presents a major infectious cause of both congenital disease during pregnancy as well as opportunistic infection in children and adults. With clear evidence that risk to the fetus varies with gestational age at the time of primary maternal infection, further research on humoral responses to primary CMV infection during pregnancy is needed.METHODSHere, systems serology tools were applied to characterize antibody responses to CMV infection in pregnant and nonpregnant women experiencing either primary or chronic infection.RESULTSWhereas strikingly different antibody profiles were observed depending on infection status, limited differences were associated with pregnancy status. Beyond known differences in IgM responses used clinically for identification of primary infection, distinctions observed in IgA and FcγR-binding antibodies and among antigen specificities accurately predicted infection status. Machine learning was used to define the transition from primary to chronic states and predict time since infection with high accuracy. Humoral responses diverged over time in an antigen-specific manner, with IgG3 responses toward tegument decreasing over time as typical of viral infections, while those directed to pentamer and glycoprotein B were lower during acute and greatest during chronic infection.CONCLUSIONIn sum, this work provides insights into the antibody response associated with CMV infection status in the context of pregnancy, revealing aspects of humoral immunity that have the potential to improve CMV diagnostics.FUNDINGCYMAF consortium and NIH NIAID.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107934","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}