ImmunityPub Date : 2024-11-12DOI: 10.1016/j.immuni.2024.10.007
Ziyi Li, Ankur Sharma
{"title":"Navigating the mutation maze: An oncogenic driver’s guide to macrophage reprogramming","authors":"Ziyi Li, Ankur Sharma","doi":"10.1016/j.immuni.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.007","url":null,"abstract":"The mechanisms by which oncogenic mutations and anatomical locations work together to influence the immune environment within tumors are not well understood. In this issue of <em>Immunity</em>, Ross et al. show that H3.3K27M diffuse midline gliomas (DMGs) are enriched with disease-associated myeloid cells (DAMs). Myeloid-targeted strategies reprogram DAMs to a homeostatic state, reduce myeloid infiltration into tumors, and prolong survival.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"63 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599881","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}
ImmunityPub Date : 2024-11-06DOI: 10.1016/j.immuni.2024.10.003
Julia Davis-Porada, Alex B. George, Nora Lam, Daniel P. Caron, Joshua I. Gray, Jenny Huang, Jennifer Hwu, Steven B. Wells, Rei Matsumoto, Masaru Kubota, YoonSeung Lee, Rory Morrison-Colvin, Isaac J. Jensen, Basak B. Ural, Namir Shaabani, Daniela Weiskopf, Alba Grifoni, Alessandro Sette, Peter A. Szabo, John R. Teijaro, Donna L. Farber
{"title":"Maintenance and functional regulation of immune memory to COVID-19 vaccines in tissues","authors":"Julia Davis-Porada, Alex B. George, Nora Lam, Daniel P. Caron, Joshua I. Gray, Jenny Huang, Jennifer Hwu, Steven B. Wells, Rei Matsumoto, Masaru Kubota, YoonSeung Lee, Rory Morrison-Colvin, Isaac J. Jensen, Basak B. Ural, Namir Shaabani, Daniela Weiskopf, Alba Grifoni, Alessandro Sette, Peter A. Szabo, John R. Teijaro, Donna L. Farber","doi":"10.1016/j.immuni.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.003","url":null,"abstract":"Memory T and B cells in tissues are essential for protective immunity. Here, we performed a comprehensive analysis of the tissue distribution, phenotype, durability, and transcriptional profile of COVID-19 mRNA vaccine-induced immune memory across blood, lymphoid organs, and lungs obtained from 63 vaccinated organ donors aged 23–86, some of whom experienced SARS-CoV-2 infection. Spike (S)-reactive memory T cells were detected in lymphoid organs and lungs and variably expressed tissue-resident markers based on infection history, and S-reactive B cells comprised class-switched memory cells resident in lymphoid organs. Compared with blood, S-reactive tissue memory T cells persisted for longer times post-vaccination and were more prevalent with age. S-reactive T cells displayed site-specific subset compositions and functions: regulatory cell profiles were enriched in tissues, while effector and cytolytic profiles were more abundant in circulation. Our findings reveal functional compartmentalization of vaccine-induced T cell memory where surveilling effectors and <em>in situ</em> regulatory responses confer protection with minimal tissue damage.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"90 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588819","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}
ImmunityPub Date : 2024-11-01DOI: 10.1016/j.immuni.2024.10.001
Megi Rexhepaj, Daniel Asarnow, Lisa Perruzza, Young-Jun Park, Barbara Guarino, Mathew Mccallum, Katja Culap, Christian Saliba, Giada Leoni, Alessio Balmelli, Courtney N. Yoshiyama, Miles S. Dickinson, Joel Quispe, Jack T. Brown, M. Alejandra Tortorici, Kaitlin R. Sprouse, Ashley L. Taylor, Davide Corti, Tyler N. Starr, Fabio Benigni, David Veesler
{"title":"Isolation and escape mapping of broadly neutralizing antibodies against emerging delta-coronaviruses","authors":"Megi Rexhepaj, Daniel Asarnow, Lisa Perruzza, Young-Jun Park, Barbara Guarino, Mathew Mccallum, Katja Culap, Christian Saliba, Giada Leoni, Alessio Balmelli, Courtney N. Yoshiyama, Miles S. Dickinson, Joel Quispe, Jack T. Brown, M. Alejandra Tortorici, Kaitlin R. Sprouse, Ashley L. Taylor, Davide Corti, Tyler N. Starr, Fabio Benigni, David Veesler","doi":"10.1016/j.immuni.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.001","url":null,"abstract":"Porcine delta-coronavirus (PDCoV) spillovers were recently detected in febrile children, underscoring the recurrent zoonoses of divergent CoVs. To date, no vaccines or specific therapeutics are approved for use in humans against PDCoV. To prepare for possible future PDCoV epidemics, we isolated PDCoV spike (S)-directed monoclonal antibodies (mAbs) from humanized mice and found that two, designated PD33 and PD41, broadly neutralized a panel of PDCoV variants. Cryoelectron microscopy (cryo-EM) structures of PD33 and PD41 in complex with the S receptor-binding domain (RBD) and ectodomain trimer revealed the epitopes recognized by these mAbs, rationalizing their broad inhibitory activity. We show that both mAbs competitively interfere with host aminopeptidase N binding to neutralize PDCoV and used deep-mutational scanning epitope mapping to associate RBD antigenic sites with mAb-mediated neutralization potency. Our results indicate a PD33-PD41 mAb cocktail may heighten the barrier to escape. PD33 and PD41 are candidates for clinical advancement against future PDCoV outbreaks.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"79 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562148","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}
ImmunityPub Date : 2024-10-29DOI: 10.1016/j.immuni.2024.10.004
Yu Wang, Shaocun Zhang, Na Kang, Lihui Dong, Haochen Ni, Sichen Liu, Siankang Chong, Zhenglin Ji, Zhengpeng Wan, Xiangjun Chen, Fei Wang, Yun Lu, Baidong Hou, Pei Tong, Hai Qi, Meng Michelle Xu, Wanli Liu
{"title":"Progressive polyadenylation and m6A modification of Ighg1 mRNA maintain IgG1 antibody homeostasis in antibody-secreting cells","authors":"Yu Wang, Shaocun Zhang, Na Kang, Lihui Dong, Haochen Ni, Sichen Liu, Siankang Chong, Zhenglin Ji, Zhengpeng Wan, Xiangjun Chen, Fei Wang, Yun Lu, Baidong Hou, Pei Tong, Hai Qi, Meng Michelle Xu, Wanli Liu","doi":"10.1016/j.immuni.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.004","url":null,"abstract":"Antigen-specific antibodies are generated by antibody-secreting cells (ASCs). How RNA post-transcriptional modification affects antibody homeostasis remains unclear. Here, we found that mRNA polyadenylations and N6-methyladenosine (m6A) modifications maintain IgG1 antibody production in ASCs. IgG heavy-chain transcripts (<em>Ighg</em>) possessed a long 3′ UTR with m6A sites, targeted by the m6A reader YTHDF1. B cell-specific deficiency of YTHDF1 impaired IgG production upon antigen immunization through reducing <em>Ighg1</em> mRNA abundance in IgG1<sup>+</sup> ASCs. Disrupting either the m6A modification of a nuclear-localized splicing intermediate <em>Ighg1</em> or the nuclear localization of YTHDF1 reduced <em>Ighg1</em> transcript stability. Single-cell RNA sequencing identified an ASC subset with excessive YTHDF1 expression in systemic lupus erythematosus patients, which was decreased upon therapy with immunosuppressive drugs. In a lupus mouse model, inhibiting YTHDF1-m6A interactions alleviated symptoms. Thus, we highlight a mechanism in ASCs to sustain the homeostasis of IgG antibody transcripts by integrating <em>Ighg1</em> mRNA polyadenylation and m6A modification.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"237 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536596","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}
ImmunityPub Date : 2024-10-23DOI: 10.1016/j.immuni.2024.09.017
Davide Mangani, Ayshwarya Subramanian, Linglin Huang, Hanning Cheng, S. Harsha Krovi, Yufan Wu, Dandan Yang, Thais G. Moreira, Giulia Escobar, Alexandra Schnell, Karen O. Dixon, Rajesh K. Krishnan, Vasundhara Singh, Raymond A. Sobel, Howard L. Weiner, Vijay K. Kuchroo, Ana C. Anderson
{"title":"Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state","authors":"Davide Mangani, Ayshwarya Subramanian, Linglin Huang, Hanning Cheng, S. Harsha Krovi, Yufan Wu, Dandan Yang, Thais G. Moreira, Giulia Escobar, Alexandra Schnell, Karen O. Dixon, Rajesh K. Krishnan, Vasundhara Singh, Raymond A. Sobel, Howard L. Weiner, Vijay K. Kuchroo, Ana C. Anderson","doi":"10.1016/j.immuni.2024.09.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.017","url":null,"abstract":"T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor T cell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature T cells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"91 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487310","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}
ImmunityPub Date : 2024-10-16DOI: 10.1016/j.immuni.2024.09.014
Seiji Kaji, Stefan A. Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O. Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Mikael Simons
{"title":"Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis","authors":"Seiji Kaji, Stefan A. Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O. Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Mikael Simons","doi":"10.1016/j.immuni.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.014","url":null,"abstract":"The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer’s disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (<em>APOE</em>) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"92 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439689","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}
ImmunityPub Date : 2024-10-14DOI: 10.1016/j.immuni.2024.09.015
Andreas Obers, Tobias Poch, Grace Rodrigues, Susan N. Christo, Luke C. Gandolfo, Raissa Fonseca, Ali Zaid, Joey En Yu Kuai, Hongjin Lai, Pirooz Zareie, Marina H. Yakou, Lachlan Dryburgh, Thomas N. Burn, James Dosser, Frank A. Buquicchio, Caleb A. Lareau, Calum Walsh, Louise Judd, Maria Rafailia Theodorou, Katharina Gutbrod, Laura K. Mackay
{"title":"Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency","authors":"Andreas Obers, Tobias Poch, Grace Rodrigues, Susan N. Christo, Luke C. Gandolfo, Raissa Fonseca, Ali Zaid, Joey En Yu Kuai, Hongjin Lai, Pirooz Zareie, Marina H. Yakou, Lachlan Dryburgh, Thomas N. Burn, James Dosser, Frank A. Buquicchio, Caleb A. Lareau, Calum Walsh, Louise Judd, Maria Rafailia Theodorou, Katharina Gutbrod, Laura K. Mackay","doi":"10.1016/j.immuni.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.015","url":null,"abstract":"Tissue-resident memory T (T<sub>RM</sub>) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common T<sub>RM</sub> cell fate remains poorly understood. Here, we show that whereas skin T<sub>RM</sub> cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive T<sub>RM</sub> cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal T<sub>RM</sub> populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated T<sub>RM</sub> cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"84 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431863","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}
ImmunityPub Date : 2024-10-14DOI: 10.1016/j.immuni.2024.09.013
Jana L. Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M. Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil KC, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P. Connelly, Shondra M. Pruett-Miller, Miguel Reina-Campos, Ananda W. Goldrath, Hongbo Chi
{"title":"CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation","authors":"Jana L. Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M. Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil KC, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P. Connelly, Shondra M. Pruett-Miller, Miguel Reina-Campos, Ananda W. Goldrath, Hongbo Chi","doi":"10.1016/j.immuni.2024.09.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.013","url":null,"abstract":"Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using <em>in vivo</em> CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8<sup>+</sup> tissue-resident memory T (T<sub>RM</sub>) cell development. T<sub>RM</sub> cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes—Flcn, Ragulator, and Rag GTPases—inhibited intestinal T<sub>RM</sub> cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to T<sub>RM</sub> programming. Further, Flcn deficiency promoted protective T<sub>RM</sub> cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor β (TGF-β)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early T<sub>RM</sub> cell formation, while Acss1 controlled T<sub>RM</sub> cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"1 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431864","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}
ImmunityPub Date : 2024-10-12DOI: 10.1016/j.immuni.2024.09.016
Nouf Aljobaily, Denise Allard, Bryant Perkins, Arielle Raugh, Tessa Galland, Yi Jing, W. Zac Stephens, Matthew L. Bettini, J. Scott Hale, Maria Bettini
{"title":"Autoimmune CD4+ T cells fine-tune TCF1 expression to maintain function and survive persistent antigen exposure during diabetes","authors":"Nouf Aljobaily, Denise Allard, Bryant Perkins, Arielle Raugh, Tessa Galland, Yi Jing, W. Zac Stephens, Matthew L. Bettini, J. Scott Hale, Maria Bettini","doi":"10.1016/j.immuni.2024.09.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.016","url":null,"abstract":"Self-reactive T cells experience chronic antigen exposure but do not exhibit signs of exhaustion. Here, we investigated the mechanisms for sustained, functioning autoimmune CD4<sup>+</sup> T cells despite chronic stimulation. Examination of T cell priming showed that CD4<sup>+</sup> T cells activated in the absence of infectious signals retained TCF1 expression. At later time points and during blockade of new T cell recruitment, most islet-infiltrating autoimmune CD4<sup>+</sup> T cells were TCF1<sup>+</sup>, although expression was reduced on a per T cell basis. The <em>Tcf7</em> locus was epigenetically modified in circulating autoimmune CD4<sup>+</sup> T cells, suggesting a pre-programmed <em>de novo</em> methylation of the locus in early stages of autoimmune CD4<sup>+</sup> T cell differentiation. This mirrored the epigenetic profile of recently recruited CD4<sup>+</sup>CD62L<sup>+</sup> T cells in the pancreas. Collectively, these data reveal a unique environment during autoimmune CD4<sup>+</sup> T cell priming that allows T cells to fine-tune TCF1 expression and maintain long-term survival and function.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142415602","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}
ImmunityPub Date : 2024-10-11DOI: 10.1016/j.immuni.2024.09.007
James L. Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Piñero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda M. Tsankova, Maria G. Castro, Matthew Schniederjan, Nitin R. Wadhwani, G. Praveen Raju, Peter Morgenstern, Oren J. Becher, Adam L. Green, Alexander M. Tsankov, Dolores Hambardzumyan
{"title":"Microglia and monocyte-derived macrophages drive progression of pediatric high-grade gliomas and are transcriptionally shaped by histone mutations","authors":"James L. Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Piñero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda M. Tsankova, Maria G. Castro, Matthew Schniederjan, Nitin R. Wadhwani, G. Praveen Raju, Peter Morgenstern, Oren J. Becher, Adam L. Green, Alexander M. Tsankov, Dolores Hambardzumyan","doi":"10.1016/j.immuni.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.007","url":null,"abstract":"Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent <em>de novo</em> mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines <em>Ccl8</em> and <em>Ccl12</em> resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"20 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405141","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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