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| Open AccessEngineered dityrosine-bonding of the RSV prefusion F protein imparts stability and potency advantages
Here the authors describe a stabilization technology that engineers crosslinks between tyrosine sidechains into a natively folded vaccine immunogen and show that immunogenicity is improved in small animal models by locking the most potently neutralizing epitopes.
- Sonal V. Gidwani
- , Devarshi Brahmbhatt
- & Mark A. Yondola
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| Open AccessFilamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models
The filamentous fungus expression system Thermothelomyces heterothallica (C1) is a protein expression system that may be useful for large scale antibody production. Here the authors characterise the production of a human monoclonal antibody that neutralises SARS-CoV-2 and compare functional properties in vitro and in animal models to antibodies produced using other methods.
- Franziska K. Kaiser
- , Mariana Gonzalez Hernandez
- & Albert D.M.E. Osterhaus
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Article
| Open AccessBacteriophage DNA induces an interrupted immune response during phage therapy in a chicken model
Bacteriophage are potential therapeutics to target bacterial infections, but recent studies suggest that bacteriophage may induce immune responses in eukaryotic cells. Here the authors show that bacteriophage DNA induces interrupted host immunity in a chicken infection model.
- Magdalena Podlacha
- , Lidia Gaffke
- & Alicja Węgrzyn
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Article
| Open AccessHLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice
The use of TCR engineered T cells holds promise for treatment of tumours, but is limited by awareness of clinically effective TCR molecules. Here the authors identify an MHC II restricted TCR that targets viral E7 of human papillomavirus type 18 and show effectivity in a murine model of solid tumour.
- Jianting Long
- , Xihe Chen
- & Yanyan Han
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Article
| Open AccessDistinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion
SARS-CoV-2 evolved into several sublineages harboring different mutations in spike. Here, the authors isolate and characterize nine SARS-CoV-2 variants and show that EG.5.1.3 has highest fitness in nasal epithelial cells, while JN.1 shows lower affinity to ACE2 and higher immune evasion compared to BA.2.86.1.
- Delphine Planas
- , Isabelle Staropoli
- & Olivier Schwartz
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Article
| Open AccessThunder-DDA-PASEF enables high-coverage immunopeptidomics and is boosted by MS2Rescore with MS2PIP timsTOF fragmentation prediction model
Human leukocyte antigen (HLA) class I peptide ligands (HLAIps) are targets for developing vaccines and immunotherapies. Here the authors report Thunder-DDA-PASEF, an immunopeptidomics method which enhances the identification of vital HLAIps crucial for vaccine and immunotherapy development.
- David Gomez-Zepeda
- , Danielle Arnold-Schild
- & Stefan Tenzer
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Article
| Open AccessDendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors
Response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) remains suboptimal, even for tumors with elevated tumor mutational burden. Here the authors generate a model of NSCLC with enhanced mutational load, showing that, while still resistant to ICIs, hypermutated tumors become sensitive to dendritic cell-targeted therapy.
- Lucía López
- , Luciano Gastón Morosi
- & Federica Benvenuti
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| Open AccessThe thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression
Regulation of thymocyte development by RNA-binding proteins is not fully characterized. Here the authors show the RBP ARPP21 interacting with the Rag1 3’-UTR to promote Rag1 expression, TCR rearrangement and an increased diversity of the TCR repertoire and that ARPP21 is down regulated by TCR stimulation.
- Meng Xu
- , Taku Ito-Kureha
- & Vigo Heissmeyer
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Article
| Open AccessMitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors
The migration of T cells into tumours and how this is regulated by metabolic pathways is not completely understood. Here the authors use human and xenograft mouse models to explore the functional changes in T cells during migration in tumours and how glycolytic and TCA cycle metabolism is involved.
- Luca Simula
- , Mattia Fumagalli
- & Emmanuel Donnadieu
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| Open AccessQuantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features
SARS-CoV-2 variants with mutations in spike have emerged during the pandemic. Magaret et al. show that in Latin America, efficacy of the Ad26.COV2.S vaccine against moderate to severe–critical COVID-19 varied by sequence features, antibody escape scores, and neutralization impacting features of the SARS-CoV-2 variant.
- Craig A. Magaret
- , Li Li
- & Peter B. Gilbert
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Article
| Open AccessAgeing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination
Factors limiting CNS remyelination with age are poorly understood. Here the authors show that aged Treg lose capacity to support CNS remyelination in mice, which can be restored in a young environment.
- Alerie Guzman de la Fuente
- , Marie Dittmer
- & Denise C. Fitzgerald
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Article
| Open AccessNon-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development
Fine-mapping has previously implicated the non-coding single nucleotide polymorphism rs117701653 as a risk variant for rheumatoid arthritis and type 1 diabetes, however its function remained unclear. Here the authors show that this variant decreases binding of the inhibitory factor SMCHD1 to enhance expression of ICOS, promoting development of potentially pathogenic T peripheral helper cells.
- Taehyeung Kim
- , Marta Martínez-Bonet
- & Peter A. Nigrovic
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Article
| Open AccessAntiviral responses induced by Tdap-IPV vaccination are associated with persistent humoral immunity to Bordetella pertussis
Epidemics of whooping cough caused by Bordetella pertussis have been seen and are linked to waning immunity globally. Here the authors explore responses to inactivated poliovirus (IPV) in the Tdap-IPV vaccine and show it stimulates early antiviral responses in monocytes and dendritic cells that are associated with long-lived pertussis antibody responses.
- Joshua Gillard
- , Madeleine Suffiotti
- & Dimitri A. Diavatopoulos
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Article
| Open AccessTick hemocytes have a pleiotropic role in microbial infection and arthropod fitness
Rolandelli et al. define how immune cells from the tick Ixodes scapularis are affected by infection and show that this cell population have distinct signatures and functions in immunity, metabolism and proliferation.
- Agustin Rolandelli
- , Hanna J. Laukaitis-Yousey
- & Joao H. F. Pedra
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Article
| Open AccessStem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice
The role of stem Leydig cells in restoration of male fertility after acute injury is not clear. In an acute injury mouse model of testicular torsion, the authors show that Stem Leydig cells can restore testicular immunological homeostasis by mitochondria transfer to macrophages in a TRPM7-mediated manner.
- Ani Chi
- , Bicheng Yang
- & Min Zhang
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Article
| Open AccessHuman IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria
Antibody based biologics are a rapidly growing class of therapeutics with interest to enhance their performance, distribution, longevity and effectivity. Here, authors report the engineering of human IgG Fc to enhance plasma half-life, mucosal distribution and killing of cancer cells and bacteria.
- Stian Foss
- , Siri A. Sakya
- & Jan Terje Andersen
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Article
| Open AccessNFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins
The immunobiology regulating the contribution of monocytes to severe COVID-19 immunopathology are not fully understood. Here the authors show that SARS-CoV-2 S1 and NP proteins differentially promote NLRP3/NLRC4 inflammasome activity, differentiation, and T cell-priming function of monocytes.
- Ilya Tsukalov
- , Ildefonso Sánchez-Cerrillo
- & Enrique Martin-Gayo
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| Open AccessMalaria blood stage infection suppresses liver stage infection via host-induced interferons but not hepcidin
Blood and liver stages of malaria parasites can affect each other, but it’s not clear how this may affect live-attenuated whole parasite vaccination. Here the authors show that malaria parasite blood stage infection subdues new infection and vaccination by suppressing growth of its liver stage via host cytokines.
- Hardik Patel
- , Nana K. Minkah
- & Stefan H. I. Kappe
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| Open AccessStructural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency
IL-11 and IL-6 signal by binding gp130. Here, Gardner et al. use cryoEM to discover how IL-11 engages gp130 and co-receptor IL-11Rα. Together with MD simulations, they provide insight into gp130 mutations that cause human immunodeficiencies.
- Scott Gardner
- , Yibo Jin
- & Doryen Bubeck
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Article
| Open AccessRHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling
Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that primarily responds to ligation of bacterial lipopolysaccharide. Here the authors suggest the intramembrane protease RHBDL4 as a regulator of TLR4 signaling.
- Julia D. Knopf
- , Susanne S. Steigleder
- & Marius K. Lemberg
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| Open AccessEvidence for immune activation in pathogenesis of the HLA class II associated disease, podoconiosis
Podoconiosis is triggered by long term barefoot exposure to volcanic red clay soil. Here, Negash et al characterise the immune profile of podoconiosis patients to show this disease is associated with high levels of immune activation and inflammation.
- Mikias Negash
- , Menberework Chanyalew
- & Melanie J. Newport
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Article
| Open AccessGene expression analyses reveal differences in children’s response to malaria according to their age
Here the authors use dual RNA sequencing to characterize host and parasite gene expression from 136 Malian children with symptomatic Plasmodium falciparum infection. They find that parasitemia levels correlate with neutrophil and T cell levels and that the child’s age correlates with innate immune gene expression as well as gametocyte levels.
- Kieran Tebben
- , Salif Yirampo
- & David Serre
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Article
| Open AccessDevelopment of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma
Rational antibody engineering can greatly improve the clinical value of therapeutic antibodies. Here authors describe ISB 1442, a fully human bispecific antibody, consisting of two targeting modules against two different epitopes on CD38, combined with a targeting module blocking CD47 and engineered effector properties, to enhance complement dependent cytotoxicity, antibody dependent cells cytotoxicity and antibody dependent cell phagocytosis to combat multiple myeloma.
- C. Grandclément
- , C. Estoppey
- & S. Sammicheli
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Article
| Open AccessALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice
Cardiac macrophage contributes to the onset of cardiac fibrosis, but the underneath mechanisms remain unclear. Here the authors show that mouse cardiac macrophages from circulating monocytes may trans-differentiate into myofibroblast under hypertensive conditions for fibrosis development, with an AKLBH5/IL11 molecular axis modulating this macrophage-to-myofibroblast transition.
- Tao Zhuang
- , Mei-Hua Chen
- & Cheng-Chao Ruan
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Article
| Open AccessLactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression
Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.
- Fatima Khan
- , Yiyun Lin
- & Peiwen Chen
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Article
| Open AccessNotch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization
Sustained exogenous Notch2 signaling prompts Follicular B cells to trans-differentiate into Marginal Zone B cells. This study reveals that under physiological conditions, Notch2 signalling regulates a fate choice in antigen activated Follicular B cells, dictating whether they develop into Germinal Center B cells or Marginal Zone B cells.
- Tea Babushku
- , Markus Lechner
- & Lothar J. Strobl
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Article
| Open AccessInactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice
Cytidine nucleotide triphosphate (CTP) is a key precursor involved in the metabolism of DNA, RNA and phospholipids. In this study, the authors examine the physiological consequences of CTP synthase (Ctps) 1 and 2 deletion in vivo and demonstrate that Ctps1 protects mice from fatal autoimmunity.
- Claire Soudais
- , Romane Schaus
- & Sylvain Latour
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Article
| Open AccessCD8+ T cell priming that is required for curative intratumorally anchored anti-4-1BB immunotherapy is constrained by Tregs
Antibodies stimulating the T cell co-activator 4-1BB (CD137) do enhance anti-tumour T cell function, but their utility is hampered by on target, off tumor toxicity. Here authors show that anchoring anti-4-1BB to tumours via fusion with the collagen binding protein LAIR diminishes systemic dissemination of the drug, and they demonstrate a curative effect in a triple-combination-therapy that relieves regulatory T cell immunosuppression in a mouse model of cancer.
- Joseph R. Palmeri
- , Brianna M. Lax
- & K. Dane Wittrup
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Article
| Open AccessDistinct transcriptomes and autocrine cytokines underpin maturation and survival of antibody-secreting cells in systemic lupus erythematosus
Autoantibody production is a hallmark of systemic lupus erythematosus (SLE). Here, the authors demonstrate that antibody-secreting cells from patients with SLE display features of premature maturation and increased survival, which are mediated by intrinsic and extrinsic programmes including autocrine APRIL.
- Weirong Chen
- , So-Hee Hong
- & Ignacio Sanz
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Article
| Open AccesssynNotch-programmed iPSC-derived NK cells usurp TIGIT and CD73 activities for glioblastoma therapy
Given its immunosuppressive effect in glioblastoma (GBM), targeting the TIGIT-CD155 axis presents an attractive therapeutic strategy. Here, the authors develop an adoptive natural killer (iNK) cells therapy with anti-CD155 synNotch-inducible CD73 antibody production to reverse the effect of TIGIT-CD155 signaling for the treatment of GBM.
- Kyle B. Lupo
- , Xue Yao
- & Sandro Matosevic
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Article
| Open AccessAltered receptor binding, antibody evasion and retention of T cell recognition by the SARS-CoV-2 XBB.1.5 spike protein
New variants of SARS-CoV-2 virus can evolve such that antibodies that recognised previous versions are not able to recognise newer versions. Here the authors characterise antibody binding to the XBB.1.5 variant and how antibodies and T cells from persons infected with earlier versions of SARS-CoV-2 are able to recognise and/or bind to the XBB.1.5 spike protein.
- Dhiraj Mannar
- , James W. Saville
- & Sriram Subramaniam
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Article
| Open AccessCoordinated inflammatory responses dictate Marburg virus control by reservoir bats
The authors show pro-inflammatory responses are needed for Marburg virus control in its natural bat reservoir, and that if reduced, humanlike disease and shedding results, suggesting that natural immunomodulatory stressors may increase spillover risk.
- Jonathan C. Guito
- , Shannon G. M. Kirejczyk
- & Jonathan S. Towner
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Article
| Open AccessComparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation
Maturation of innate immune cells is a graded stereotypic process which is often conserved across species. Here authors label distinct neutrophil leukocyte developmental stages via generating combinations of transgenic zebrafish reporter strains, followed by transcriptome analysis of different neutrophil maturation stages and comparison to the gene expression profile of developing neutrophils from humans and mice.
- Stefanie Kirchberger
- , Mohamed R. Shoeb
- & Martin Distel
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Article
| Open AccessQ586B2 is a crucial virulence factor during the early stages of Trypanosoma brucei infection that is conserved amongst trypanosomatids
Sleeping sickness caused by African trypanosome parasites induces a chronic, and potentially lethal, infection in humans. Here, the authors uncover a conserved protein, Q586B2, playing an important regulatory role in Trypanosomatid infection establishment.
- Benoit Stijlemans
- , Patrick De Baetselier
- & Carl De Trez
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Article
| Open AccessType 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice
Although continuous activity of Foxo transcription factors substantially increase the life span of species such as Hydra vulgaris, these proteins have never been implicated in mammalian aging. In this study, the authors demonstrate that, with age, Foxo1 is down-regulated in mouse T lymphocytes and associated with exhaustion.
- Aurélie Durand
- , Nelly Bonilla
- & Bruno Lucas
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Article
| Open AccessHuman cytomegalovirus exploits STING signaling and counteracts IFN/ISG induction to facilitate infection of dendritic cells
Human cytomegalovirus (HCMV) is a ubiquitous pathogen associated with morbidity and mortality in the immunocompromised or immunonaive context. Here the authors show that HCMV exploits STING signalling and subverts the interferon response to support infection of monocyte derive dendritic cells.
- Bibiana Costa
- , Jennifer Becker
- & Ulrich Kalinke
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Article
| Open AccessNINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress
Fevers are known to be both beneficial and detrimental in disease, but the fundamental innate immune mechanisms driving pathology in this context remain unclear. Here, the authors show that a combination of LPS and heat stress induces inflammatory cell death, PANoptosis, that is dependent on the executioner molecule Ninjurin 1 (Ninj1) to release inflammatory molecules and drive pathogenesis.
- Joo-Hui Han
- , Rajendra Karki
- & Thirumala-Devi Kanneganti
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Article
| Open AccessSerum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma
The reasons for why hepatocellular carcinoma (HCC) is unresponsive to anti-PD-1 inhibition in some patients is not fully understood. Here the authors use human samples and mice tumour models to implicate serum amyloid A and STAT3 signalling involvement in the resistance to anti-PD1 immunotherapy in HCC.
- Meng He
- , Yongxiang Liu
- & Ning Lyu
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Article
| Open AccessS-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens
The generation of reactive oxygen and nitrogen species is an critical part of host defense against microbial infection. Here, Jia et al, characterize the mechanisms by which reactive nitrogen species can modulate innate immunity.
- Mutian Jia
- , Li Chai
- & Wei Zhao
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Article
| Open AccessIntestinal stroma guides monocyte differentiation to macrophages through GM-CSF
Stromal cells are key players in immune cell homeostasis. Here, the authors decipher subset-specific human stromal responses in inflammatory bowel disease and suggest that intestinal PDGFRA+CD142−/low fibroblasts guide monocyte transition to macrophages in human gut through GM-CSF.
- Egle Kvedaraite
- , Magda Lourda
- & Mattias Svensson
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Article
| Open AccessNucleocapsid protein-specific monoclonal antibodies protect mice against Crimean-Congo hemorrhagic fever virus
There are limited treatment options for infection with Crimean-Congo hemorrhagic fever virus in humans. Here, the authors show that a monoclonal antibody targeting the highly conserved viral nucleocapsid protein provides protective effects in a mouse model of infection.
- Aura R. Garrison
- , Vanessa Moresco
- & Joseph W. Golden
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Article
| Open AccessMarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution
Three-dimensional analysis of the intact bone marrow within whole long bones remains very challenging. Here, the authors present a method that stabilizes the marrow and provides subcellular resolution of fluorescent signals throughout the murine femur.
- Till Fabian Mertens
- , Alina Tabea Liebheit
- & Anja Erika Hauser
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Article
| Open AccessPrior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection
Flavivirus infection or vaccination can induce cross-reactive immune responses. Here, the authors show how previous immunization with the tick-borne encephalitis virus vaccine affects the immune response to the yellow fever vaccine, suggesting that the yellow fever vaccine virus conceals epitopes shared with other flaviviruses in flavivirus-naive but not flavivirus-pre-exposed individuals.
- Antonio Santos-Peral
- , Fabian Luppa
- & Simon Rothenfusser
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Article
| Open AccessThe ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment
The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.
- Elizabeth L. Hardaker
- , Emilio Sanseviero
- & Simon T. Barry
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Article
| Open AccessNAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling.
- Yannick Fotio
- , Alex Mabou Tagne
- & Daniele Piomelli
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Article
| Open AccessSingle-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model
Classical monocytes can differentiate into pro-inflammatory or pro-resolving macrophages. Here the authors characterise mouse macrophage differentiation and show that Ly6Chi classical monocytes can differentiate into Ly6Clo pro-resolving macrophages which are involved in the resolution of skin allergic inflammation.
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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Article
| Open AccessTargeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis
Triggering the PD-1/PD-L1 immune checkpoint is an attractive therapeutic approach in inflammatory bowel disease, and PD-L1, conjugated to the Fc part of an immunoglobulin (PD-L1-Fc) has been shown to be effective in mouse models. Here authors show that fusing to reactive oxygen species (ROS)-responsive nanoparticles improves effect of PD-L1-Fc due to targeting to inflammation sites, while systemic toxicity is reduced.
- Xudong Tang
- , Yangyang Shang
- & Lei Chen
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Article
| Open AccessAdjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial
Immunotherapy using dendritic cell (DC)-based vaccination has been exploited in the clinic for cancer treatment. Here the authors report the results of a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived DC cell-based therapy in patients with stage IIIB and IIIC melanoma.
- Kalijn F. Bol
- , Gerty Schreibelt
- & I. Jolanda M. de Vries
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Article
| Open AccessImmune signature of Chlamydia vaccine CTH522/CAF®01 translates from mouse-to-human and induces durable protection in mice
Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate.
- Anja W. Olsen
- , Ida Rosenkrands
- & Frank Follmann
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