Pub Date : 2024-05-29DOI: 10.1126/scitranslmed.adn2199
José Victor Zambrana, Chloe M. Hasund, Rosemary A. Aogo, Sandra Bos, Sonia Arguello, Karla Gonzalez, Damaris Collado, Tatiana Miranda, Guillermina Kuan, Aubree Gordon, Angel Balmaseda, Leah C. Katzelnick, Eva Harris
Infection with any of the four dengue virus serotypes (DENV1–4) can protect against or enhance subsequent dengue depending on preexisting antibodies and infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) is associated with increased risk of DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by DENV1–4 in a pediatric Nicaraguan cohort. Of 3412 participants in 2022, 10.6% experienced dengue cases caused by DENV1 (n = 139), DENV4 (n = 133), DENV3 (n = 54), DENV2 (n = 9), or an undetermined serotype (n = 39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since last infection, and year, and repeat measurements were used to predict disease risk. Compared with flavivirus-naïve participants, primary ZIKV infection was associated with increased risk of disease caused by DENV4 (relative risk = 2.62, 95% confidence interval: 1.48 to 4.63) and DENV3 (2.90, 1.34 to 6.27), but not DENV1 infection. Primary DENV infection or DENV followed by ZIKV infection was also associated with increased risk of DENV4 disease. We reanalyzed 19 years of cohort data and demonstrated that prior flavivirus immunity and antibody titer had distinct associations with disease risk depending on incoming serotype. We thus find that prior ZIKV infection, like prior DENV infection, is associated with increased risk of disease with certain DENV serotypes. Cross-reactivity among flaviviruses should be considered when assessing vaccine safety and efficacy.
{"title":"Primary exposure to Zika virus is linked with increased risk of symptomatic dengue virus infection with serotypes 2, 3, and 4, but not 1","authors":"José Victor Zambrana, Chloe M. Hasund, Rosemary A. Aogo, Sandra Bos, Sonia Arguello, Karla Gonzalez, Damaris Collado, Tatiana Miranda, Guillermina Kuan, Aubree Gordon, Angel Balmaseda, Leah C. Katzelnick, Eva Harris","doi":"10.1126/scitranslmed.adn2199","DOIUrl":"10.1126/scitranslmed.adn2199","url":null,"abstract":"<div >Infection with any of the four dengue virus serotypes (DENV1–4) can protect against or enhance subsequent dengue depending on preexisting antibodies and infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) is associated with increased risk of DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by DENV1–4 in a pediatric Nicaraguan cohort. Of 3412 participants in 2022, 10.6% experienced dengue cases caused by DENV1 (<i>n</i> = 139), DENV4 (<i>n</i> = 133), DENV3 (<i>n</i> = 54), DENV2 (<i>n</i> = 9), or an undetermined serotype (<i>n</i> = 39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since last infection, and year, and repeat measurements were used to predict disease risk. Compared with flavivirus-naïve participants, primary ZIKV infection was associated with increased risk of disease caused by DENV4 (relative risk = 2.62, 95% confidence interval: 1.48 to 4.63) and DENV3 (2.90, 1.34 to 6.27), but not DENV1 infection. Primary DENV infection or DENV followed by ZIKV infection was also associated with increased risk of DENV4 disease. We reanalyzed 19 years of cohort data and demonstrated that prior flavivirus immunity and antibody titer had distinct associations with disease risk depending on incoming serotype. We thus find that prior ZIKV infection, like prior DENV infection, is associated with increased risk of disease with certain DENV serotypes. Cross-reactivity among flaviviruses should be considered when assessing vaccine safety and efficacy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adn2199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174320","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}
Many psychiatric disorders exhibit sex differences, but the underlying mechanisms remain poorly understood. We analyzed transcriptomics data from 2160 postmortem adult prefrontal cortex brain samples from the PsychENCODE consortium in a sex-stratified study design. We compared transcriptomics data of postmortem brain samples from patients with schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) with transcriptomics data of postmortem control brains from individuals without a known history of psychiatric disease. We found that brain samples from females with SCZ, BD, and ASD showed a higher burden of transcriptomic dysfunction than did brain samples from males with these disorders. This observation was supported by the larger number of differentially expressed genes (DEGs) and a greater magnitude of gene expression changes observed in female versus male brain specimens. In addition, female patient brain samples showed greater overall connectivity dysfunction, defined by a higher proportion of gene coexpression modules with connectivity changes and higher connectivity burden, indicating a greater degree of gene coexpression variability. We identified several gene coexpression modules enriched in sex-biased DEGs and identified genes from a genome-wide association study that were involved in immune and synaptic functions across different brain cell types. We found a number of genes as hubs within these modules, including those encoding SCN2A, FGF14, and C3. Our results suggest that in the context of psychiatric diseases, males and females exhibit different degrees of transcriptomic dysfunction and implicate immune and synaptic-related pathways in these sex differences.
{"title":"Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders","authors":"Yan Xia, Cuihua Xia, Yi Jiang, Yu Chen, Jiaqi Zhou, Rujia Dai, Cong Han, Zhongzheng Mao, PsychENCODE Consortium, Chunyu Liu, Chao Chen","doi":"10.1126/scitranslmed.adh9974","DOIUrl":"10.1126/scitranslmed.adh9974","url":null,"abstract":"<div >Many psychiatric disorders exhibit sex differences, but the underlying mechanisms remain poorly understood. We analyzed transcriptomics data from 2160 postmortem adult prefrontal cortex brain samples from the PsychENCODE consortium in a sex-stratified study design. We compared transcriptomics data of postmortem brain samples from patients with schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) with transcriptomics data of postmortem control brains from individuals without a known history of psychiatric disease. We found that brain samples from females with SCZ, BD, and ASD showed a higher burden of transcriptomic dysfunction than did brain samples from males with these disorders. This observation was supported by the larger number of differentially expressed genes (DEGs) and a greater magnitude of gene expression changes observed in female versus male brain specimens. In addition, female patient brain samples showed greater overall connectivity dysfunction, defined by a higher proportion of gene coexpression modules with connectivity changes and higher connectivity burden, indicating a greater degree of gene coexpression variability. We identified several gene coexpression modules enriched in sex-biased DEGs and identified genes from a genome-wide association study that were involved in immune and synaptic functions across different brain cell types. We found a number of genes as hubs within these modules, including those encoding <i>SCN2A</i>, <i>FGF14</i>, and <i>C3</i>. Our results suggest that in the context of psychiatric diseases, males and females exhibit different degrees of transcriptomic dysfunction and implicate immune and synaptic-related pathways in these sex differences.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088757","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}
Pub Date : 2024-05-22DOI: 10.1126/scitranslmed.adj3385
Zhuo Chen, Eiichiro Satake, Marcus G. Pezzolesi, Zaipul I. Md Dom, Devorah Stucki, Hiroki Kobayashi, Anna Syreeni, Adam T. Johnson, Xiwei Wu, Emma H. Dahlström, Jaxon B. King, Per-Henrik Groop, Stephen S. Rich, Niina Sandholm, Andrzej S. Krolewski, Rama Natarajan
Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5′-cytosine-phosphate-guanine-3′ loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10−14. In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.
{"title":"Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes","authors":"Zhuo Chen, Eiichiro Satake, Marcus G. Pezzolesi, Zaipul I. Md Dom, Devorah Stucki, Hiroki Kobayashi, Anna Syreeni, Adam T. Johnson, Xiwei Wu, Emma H. Dahlström, Jaxon B. King, Per-Henrik Groop, Stephen S. Rich, Niina Sandholm, Andrzej S. Krolewski, Rama Natarajan","doi":"10.1126/scitranslmed.adj3385","DOIUrl":"10.1126/scitranslmed.adj3385","url":null,"abstract":"<div >Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5′-cytosine-phosphate-guanine-3′ loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at <i>P</i> = 6.62 × 10<sup>−14</sup>. In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082223","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}
Pub Date : 2024-05-22DOI: 10.1126/scitranslmed.adl2720
Christiane R. Stadler, Ursula Ellinghaus, Leyla Fischer, Hayat Bähr-Mahmud, Martin Rao, Claudia Lindemann, Anuhar Chaturvedi, Caroline Scharf, Imke Biermann, Bernhard Hebich, Alexandra Malz, Georg Beresin, Georg Falck, Aline Häcker, Astrid Houben, Michael Erdeljan, Kristina Wolf, Maximilian Kullmann, Philip Chang, Özlem Türeci, Uğur Şahin
We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)–formulated RNA (RNA-LNP) encoding a T cell–engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell–specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-μg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530).
{"title":"Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6","authors":"Christiane R. Stadler, Ursula Ellinghaus, Leyla Fischer, Hayat Bähr-Mahmud, Martin Rao, Claudia Lindemann, Anuhar Chaturvedi, Caroline Scharf, Imke Biermann, Bernhard Hebich, Alexandra Malz, Georg Beresin, Georg Falck, Aline Häcker, Astrid Houben, Michael Erdeljan, Kristina Wolf, Maximilian Kullmann, Philip Chang, Özlem Türeci, Uğur Şahin","doi":"10.1126/scitranslmed.adl2720","DOIUrl":"10.1126/scitranslmed.adl2720","url":null,"abstract":"<div >We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)–formulated RNA (RNA-LNP) encoding a T cell–engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell–specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-μg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adl2720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082230","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}
Pub Date : 2024-05-22DOI: 10.1126/scitranslmed.adj4504
David R. Martinez, Fernando R. Moreira, Nicholas J. Catanzaro, Meghan V. Diefenbacher, Mark R. Zweigart, Kendra L. Gully, Gabriela De la Cruz, Ariane J. Brown, Lily E. Adams, Boyd Yount, Thomas J. Baric, Michael L. Mallory, Helen Conrad, Samantha R. May, Stephanie Dong, D. Trevor Scobey, Cameron Nguyen, Stephanie A. Montgomery, Jason K. Perry, Darius Babusis, Kimberly T. Barrett, Anh-Hoa Nguyen, Anh-Quan Nguyen, Rao Kalla, Roy Bannister, Joy Y. Feng, Tomas Cihlar, Ralph S. Baric, Richard L. Mackman, John P. Bilello, Alexandra Schäfer, Timothy P. Sheahan
Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV–related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.
{"title":"The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses","authors":"David R. Martinez, Fernando R. Moreira, Nicholas J. Catanzaro, Meghan V. Diefenbacher, Mark R. Zweigart, Kendra L. Gully, Gabriela De la Cruz, Ariane J. Brown, Lily E. Adams, Boyd Yount, Thomas J. Baric, Michael L. Mallory, Helen Conrad, Samantha R. May, Stephanie Dong, D. Trevor Scobey, Cameron Nguyen, Stephanie A. Montgomery, Jason K. Perry, Darius Babusis, Kimberly T. Barrett, Anh-Hoa Nguyen, Anh-Quan Nguyen, Rao Kalla, Roy Bannister, Joy Y. Feng, Tomas Cihlar, Ralph S. Baric, Richard L. Mackman, John P. Bilello, Alexandra Schäfer, Timothy P. Sheahan","doi":"10.1126/scitranslmed.adj4504","DOIUrl":"10.1126/scitranslmed.adj4504","url":null,"abstract":"<div >Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV–related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (M<sup>pro</sup>) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082234","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}
Pub Date : 2024-05-22DOI: 10.1126/scitranslmed.adk1358
Jeremy M. Sullivan, Anna M. Bagnell, Jonathan Alevy, Elvia Mena Avila, Ljubica Mihaljević, Pamela C. Saavedra-Rivera, Lingling Kong, Jennifer S. Huh, Brett A. McCray, William H. Aisenberg, Aamir R. Zuberi, Laurent Bogdanik, Cathleen M. Lutz, Zhaozhu Qiu, Katharina A. Quinlan, Peter C. Searson, Charlotte J. Sumner
Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease. To gain insights into the cellular basis of these disorders, we generated knock-in mouse models of TRPV4 channelopathy by introducing two disease-causing mutations (R269C and R232C) into the endogenous mouse Trpv4 gene. TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss. Genetic deletion of the mutant Trpv4 allele from endothelial cells (but not neurons, glia, or muscle) rescued these phenotypes. Symptomatic mutant mice exhibited focal disruptions of blood–spinal cord barrier (BSCB) integrity, associated with a gain of function of mutant TRPV4 channel activity in neural vascular endothelial cells (NVECs) and alterations of NVEC tight junction structure. Systemic administration of a TRPV4-specific antagonist abrogated channel-mediated BSCB impairments and provided a marked phenotypic rescue of symptomatic mutant mice. Together, our findings show that mutant TRPV4 channels can drive motor neuron degeneration in a non–cell autonomous manner by precipitating focal breakdown of the BSCB. Further, these data highlight the reversibility of TRPV4-mediated BSCB impairments and identify a potential therapeutic strategy for patients with TRPV4 mutations.
{"title":"Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice","authors":"Jeremy M. Sullivan, Anna M. Bagnell, Jonathan Alevy, Elvia Mena Avila, Ljubica Mihaljević, Pamela C. Saavedra-Rivera, Lingling Kong, Jennifer S. Huh, Brett A. McCray, William H. Aisenberg, Aamir R. Zuberi, Laurent Bogdanik, Cathleen M. Lutz, Zhaozhu Qiu, Katharina A. Quinlan, Peter C. Searson, Charlotte J. Sumner","doi":"10.1126/scitranslmed.adk1358","DOIUrl":"10.1126/scitranslmed.adk1358","url":null,"abstract":"<div >Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease. To gain insights into the cellular basis of these disorders, we generated knock-in mouse models of TRPV4 channelopathy by introducing two disease-causing mutations (R269C and R232C) into the endogenous mouse <i>Trpv4</i> gene. TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss. Genetic deletion of the mutant <i>Trpv4</i> allele from endothelial cells (but not neurons, glia, or muscle) rescued these phenotypes. Symptomatic mutant mice exhibited focal disruptions of blood–spinal cord barrier (BSCB) integrity, associated with a gain of function of mutant TRPV4 channel activity in neural vascular endothelial cells (NVECs) and alterations of NVEC tight junction structure. Systemic administration of a TRPV4-specific antagonist abrogated channel-mediated BSCB impairments and provided a marked phenotypic rescue of symptomatic mutant mice. Together, our findings show that mutant TRPV4 channels can drive motor neuron degeneration in a non–cell autonomous manner by precipitating focal breakdown of the BSCB. Further, these data highlight the reversibility of TRPV4-mediated BSCB impairments and identify a potential therapeutic strategy for patients with TRPV4 mutations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082218","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}
Pub Date : 2024-05-16DOI: 10.1126/scitranslmed.adn0223
Christopher A. Cottrell, Xiaozhen Hu, Jeong Hyun Lee, Patrick Skog, Sai Luo, Claudia T. Flynn, Katherine R. McKenney, Jonathan Hurtado, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Elise Landais, Sebastian Raemisch, Xuejun Chen, Sabyasachi Baboo, Sunny Himansu, Jolene K. Diedrich, Hongying Duan, Cheng Cheng, Torben Schiffner, Daniel L. V. Bader, Daniel W. Kulp, Ryan Tingle, Erik Georgeson, Saman Eskandarzadeh, Nushin Alavi, Danny Lu, Troy Sincomb, Michael Kubitz, Tina-Marie Mullen, John R. Yates III, James C. Paulson, John R. Mascola, Frederick W. Alt, Bryan Briney, Devin Sok, William R. Schief
A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.
{"title":"Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice","authors":"Christopher A. Cottrell, Xiaozhen Hu, Jeong Hyun Lee, Patrick Skog, Sai Luo, Claudia T. Flynn, Katherine R. McKenney, Jonathan Hurtado, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Elise Landais, Sebastian Raemisch, Xuejun Chen, Sabyasachi Baboo, Sunny Himansu, Jolene K. Diedrich, Hongying Duan, Cheng Cheng, Torben Schiffner, Daniel L. V. Bader, Daniel W. Kulp, Ryan Tingle, Erik Georgeson, Saman Eskandarzadeh, Nushin Alavi, Danny Lu, Troy Sincomb, Michael Kubitz, Tina-Marie Mullen, John R. Yates III, James C. Paulson, John R. Mascola, Frederick W. Alt, Bryan Briney, Devin Sok, William R. Schief","doi":"10.1126/scitranslmed.adn0223","DOIUrl":"10.1126/scitranslmed.adn0223","url":null,"abstract":"<div >A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01<sub>B</sub> was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953696","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}
Pub Date : 2024-05-15DOI: 10.1126/scitranslmed.adl4497
Vitor M. Pereira, Pedro Lylyk, Nicole Cancelliere, Pedro N. Lylyk, Ivan Lylyk, Vania Anagnostakou, Carlos Bleise, Hidehisa Nishi, Mark Epshtein, Robert M. King, Mohammed Salman Shazeeb, Ajit S. Puri, Conrad W. Liang, Ricardo A. Hanel, Julian Spears, Thomas R. Marotta, Demetrius K. Lopes, Matthew J. Gounis, Giovanni J. Ughi
Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate procedural decision-making. In a human study involving 32 patients, we introduced the clinical application of a miniaturized endovascular neuro optical coherence tomography (nOCT) imaging probe. This technology was designed to navigate the tortuous paths of the cerebrovascular circulation and to offer high-resolution imaging in situ. The nOCT probe is compatible with standard neurovascular microcatheters, integrating with the procedural workflow used in clinical routine. Equipped with a miniaturized optical fiber and a distal lens, the probe illuminates the tissue and collects the backscattered, near-infrared light. While rotating the fiber and the lens at high speed, the probe is rapidly retracted, creating a spiral-shaped light pattern to comprehensively capture the arterial wall and implanted devices. Using nOCT, we demonstrated volumetric microscopy of cerebral arteries in patients undergoing endovascular procedures. We imaged the anterior and posterior circulation of the brain, including distal segments of the internal carotid and middle-cerebral arteries, as well as the vertebral, basilar, and posterior cerebral arteries. We captured a broad spectrum of neurovascular pathologies, such as brain aneurysms, ischemic stroke, arterial stenoses, dissections, and intracranial atherosclerotic disease. nOCT offered artifact-free, high-resolution visualizations of intracranial artery pathology and neurovascular devices.
{"title":"Volumetric microscopy of cerebral arteries with a miniaturized optical coherence tomography imaging probe","authors":"Vitor M. Pereira, Pedro Lylyk, Nicole Cancelliere, Pedro N. Lylyk, Ivan Lylyk, Vania Anagnostakou, Carlos Bleise, Hidehisa Nishi, Mark Epshtein, Robert M. King, Mohammed Salman Shazeeb, Ajit S. Puri, Conrad W. Liang, Ricardo A. Hanel, Julian Spears, Thomas R. Marotta, Demetrius K. Lopes, Matthew J. Gounis, Giovanni J. Ughi","doi":"10.1126/scitranslmed.adl4497","DOIUrl":"10.1126/scitranslmed.adl4497","url":null,"abstract":"<div >Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate procedural decision-making. In a human study involving 32 patients, we introduced the clinical application of a miniaturized endovascular neuro optical coherence tomography (<i>n</i>OCT) imaging probe. This technology was designed to navigate the tortuous paths of the cerebrovascular circulation and to offer high-resolution imaging in situ. The <i>n</i>OCT probe is compatible with standard neurovascular microcatheters, integrating with the procedural workflow used in clinical routine. Equipped with a miniaturized optical fiber and a distal lens, the probe illuminates the tissue and collects the backscattered, near-infrared light. While rotating the fiber and the lens at high speed, the probe is rapidly retracted, creating a spiral-shaped light pattern to comprehensively capture the arterial wall and implanted devices. Using <i>n</i>OCT, we demonstrated volumetric microscopy of cerebral arteries in patients undergoing endovascular procedures. We imaged the anterior and posterior circulation of the brain, including distal segments of the internal carotid and middle-cerebral arteries, as well as the vertebral, basilar, and posterior cerebral arteries. We captured a broad spectrum of neurovascular pathologies, such as brain aneurysms, ischemic stroke, arterial stenoses, dissections, and intracranial atherosclerotic disease. <i>n</i>OCT offered artifact-free, high-resolution visualizations of intracranial artery pathology and neurovascular devices.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945181","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}
Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.
本质性震颤（ET）是最常见的运动障碍，其主要特征是动作性震颤，即具有特定频率的不自主节律性运动。然而，震颤频率编码的神经元机制仍有待探索。在这里，我们利用体内电生理学、光遗传学和同步运动追踪技术，在 Grid2dupE3 小鼠模型中研究了橄榄小脑中的神经元活动是否以及如何决定本质性震颤的频率。我们报告说，震颤频率是由这些小鼠小脑橄榄核内群体神经元发射的时间一致性编码的，从而导致频率依赖性小脑振荡和震颤。这种机制既精确又可推广，使我们能够利用小脑深核的光遗传刺激诱导野生型小鼠出现频率特异性震颤，或改变震颤小鼠的震颤频率。在ET患者中，我们发现对丘脑的深部脑刺激抑制了震颤症状，但并没有消除通过脑电图测量到的小脑振荡，这表明小脑中与震颤相关的振荡并不需要与丘脑的相互影响。干扰频率的经颅交变电流刺激小脑可抑制震颤振幅，证实了小脑在 ET 患者中的频率调节作用。这些发现为刺激小脑治疗本质性震颤提供了神经动力学基础。
{"title":"Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients","authors":"Yi-Mei Wang, Chia-Wei Liu, Shun-Ying Chen, Liang-Yin Lu, Wen-Chuan Liu, Jia-Huei Wang, Chun-Lun Ni, Shi-Bing Wong, Ami Kumar, Jye-Chang Lee, Sheng-Han Kuo, Shun-Chi Wu, Ming-Kai Pan","doi":"10.1126/scitranslmed.adl1408","DOIUrl":"10.1126/scitranslmed.adl1408","url":null,"abstract":"<div >Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the <i>Grid2</i><sup><i>dupE3</i></sup> mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944784","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}
Pub Date : 2024-05-15DOI: 10.1126/scitranslmed.adi2952
Shi Yong Neo, Le Tong, Joni Chong, Yaxuan Liu, Xu Jing, Mariana M. S. Oliveira, Yi Chen, Ziqing Chen, Keene Lee, Nutsa Burduli, Xinsong Chen, Juan Gao, Ran Ma, Jia Pei Lim, Jianxin Huo, Shengli Xu, Evren Alici, Stina L. Wickström, Felix Haglund, Johan Hartman, Arnika K. Wagner, Yihai Cao, Rolf Kiessling, Kong Peng Lam, Lisa S. Westerberg, Andreas Lundqvist
Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell–to–myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell–derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with b2m-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and IL-6 KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell–mediated mechanism that drives the development of MDSCs during tumor immune escape.
自然杀伤（NK）细胞除了具有杀伤特性外，还在塑造肿瘤微环境方面发挥着不可或缺的作用。通过免疫基因解卷积，本研究揭示了免疫检查点疗法无反应者中NK细胞与髓源性抑制细胞（MDSCs）之间的相互作用。鉴于NK细胞与类髓鞘细胞相互作用的机制在很大程度上仍然未知，我们试图研究NK细胞与抑制性类髓鞘细胞之间的交叉对话。与肿瘤经验丰富的 NK 细胞接触后，单核细胞和中性粒细胞显示出与 MDSC 相关的抑制因子表达增加，同时抑制 T 细胞的能力也增强了。伴随这些变化的是单核细胞抗原呈递功能受损和中性粒细胞ER应激反应增强。在一组肉瘤和乳腺癌患者中，肿瘤浸润NK细胞产生的白细胞介素-6（IL-6）与MDSCs表达的S100A8/9和精氨酸酶-1相关。同时，NK细胞衍生的IL-6与主要组织相容性复合体I类表达较高的肿瘤相关，我们通过b2m基因敲除（KO）肿瘤小鼠模型进一步验证了这一点。同样，在合成野生型和IL-6 KO小鼠模型中，我们也证明了MDSCs的积累受这种调节性NK细胞存在的影响。抑制IL-6/信号转导和激活转录3（STAT3）轴可减轻对T细胞反应的抑制，从而减少肿瘤生长和转移扩散。这些结果共同描述了在肿瘤免疫逃逸过程中驱动 MDSCs 发展的 NK 细胞介导的关键机制。
{"title":"Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis","authors":"Shi Yong Neo, Le Tong, Joni Chong, Yaxuan Liu, Xu Jing, Mariana M. S. Oliveira, Yi Chen, Ziqing Chen, Keene Lee, Nutsa Burduli, Xinsong Chen, Juan Gao, Ran Ma, Jia Pei Lim, Jianxin Huo, Shengli Xu, Evren Alici, Stina L. Wickström, Felix Haglund, Johan Hartman, Arnika K. Wagner, Yihai Cao, Rolf Kiessling, Kong Peng Lam, Lisa S. Westerberg, Andreas Lundqvist","doi":"10.1126/scitranslmed.adi2952","DOIUrl":"10.1126/scitranslmed.adi2952","url":null,"abstract":"<div >Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell–to–myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell–derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with <i>b2m</i>-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and <i>IL-6</i> KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell–mediated mechanism that drives the development of MDSCs during tumor immune escape.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":17.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944794","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}
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