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Article
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Monoclonal antibodies targeting sites in respiratory syncytial virus attachment G protein provide protection against RSV-A and RSV-B in mice
Effective antibodies targeting various respiratory syncytial virus (RSV) proteins are needed to address public health burden of RSV. Here the authors shows that in addition to the currently approved F-targeting monoclonal antibodies, anti-G cross-reactive monoclonal antibodies to RSV-A and RSV-B strains can provide cross-protection and prevent from RSV disease.
- Youri Lee
- , Laura Klenow
- & Surender Khurana
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Article
| Open Access
Human 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 Access
CD8+ 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 Access
COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase
Less is known about SARS-CoV-2 infection in unstudied geographical areas such as sub-Saharan Africa. Here the authors use multi-omics to characterize the immune response to SARS-CoV-2 in Uganda and consider how people living with HIV immunologically differentially respond to the virus.
- Matthew J. Cummings
- , Barnabas Bakamutumaho
- & Max R. O’Donnell
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Article
| Open Access
Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma
The anti-CD38 monoclonal antibody Daratumumab is approved for the treatment of multiple myeloma but efficiency is curtailed by secondary resistance. Here authors show that the antibody-dependent cellular cytotoxicity, which is the main mechanism of action for Daratumumab, is regulated by KDM6A via Histone H3 K27 methylation of CD38 and CD48, downregulation of which leads to drug resistance.
- Jiye Liu
- , Lijie Xing
- & Kenneth C. Anderson
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Article
| Open Access
Smith-specific regulatory T cells halt the progression of lupus nephritis
Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.
- Peter J. Eggenhuizen
- , Rachel M. Y. Cheong
- & Joshua D. Ooi
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Article
| Open Access
WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease
Fibroblast heterogeneity is a recognized feature in chronic kidney disease, and although fibrosis is integrant to the pathology, it is lesser known which of the fibroblast populations contribute. Here authors describe a population of proinflammatory fibroblasts, which are found in close proximity to macrophages and may facilitate their recruitment and acquisition of a FOLR2+, pathogenic phenotype.
- Camille Cohen
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Review Article
| Open Access
Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology
- Nieves Montenegro-Navarro
- , Claudia García-Báez
- & Melissa García-Caballero
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Article
| Open Access
An in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases
Immune checkpoints are critical in maintaining self-tolerance and their therapeutic modulation can be achieved in autoimmune diseases. Here the authors present an in situ dual-anchoring approach that targets PD-L1 and show effects in animal models of autoimmunity.
- Shenqiang Wang
- , Ying Zhang
- & Jicheng Yu
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Article
| Open Access
Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV± cancer
Current biological models for examining cancer immunobiology in a HIV infected context are lacking. Here the authors use a human-derived microphysiological model to represent the HIV immune system and assess the ability of transferred populations of NK cells in the targeting of tumours.
- Jose M. Ayuso
- , Mehtab Farooqui
- & David J. Beebe
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Article
| Open Access
Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model
Successful engraftment of human hematopoietic stem cells during gene therapy requires myeloablative conditioning of the recipient, at the expense of toxicity. Authors show here that a single-dose of anti-CD117 antibody-drug conjugate achieves similar engraftment results as traditional multi-dose busulfan conditioning but preserves fertility in a non-human primate model.
- Naoya Uchida
- , Ulana Stasula
- & John F. Tisdale
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Article
| Open Access
Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment
The emergency of a high frequency of early memory T cells has been associated with clinical success of CAR T cell therapy. Here the authors show that target cancer cells stressed by disulfiram/copper complexes and ionizing radiation favour the reprogramming of CAR T cells that acquire memory-like characteristics, associated with prolonged anti-tumor response in preclinical solid tumor models.
- Yufeng Wang
- , David L. Drum
- & Xinhui Wang
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Article
| Open Access
Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype
Acquired resistance to immune checkpoint inhibitors limits therapeutic success in non-small-cell lung cancer, however, the underpinning immune parameters are largely unknown. Here authors distinguish resistance types based on immune cell infiltration, immune checkpoint molecule and cytokine expression level, using paired samples from patients in the sensitive and in the resistant disease phase.
- Stefanie Hiltbrunner
- , Lena Cords
- & Alessandra Curioni-Fontecedro
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Article
| Open Access
Intradermal but not intramuscular modified vaccinia Ankara immunizations protect against intravaginal tier2 simian-human immunodeficiency virus challenges in female macaques
The route of vaccine administration is known to effect the induction of immune response and the quality of such immunity. Here the authors show that intradermal but not intramuscular vaccination using live-attenuated vaccinia-based SHIV vaccine confers protection in the SHIV model in female macaques and characterise the induced immune response.
- Venkata S. Bollimpelli
- , Pradeep B. J Reddy
- & Rama R. Amara
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Article
| Open Access
Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting
Targeting solid tumours by chimeric antigen receptor (CAR) T cells require strategies that improve trafficking and effector function of these cells in the immunologically hostile cancer microenvironment. Here, authors show that CAR T cells engineered with incorporation of the CD28 transmembrane domain to the 4-1BB costimulatory domain and a membrane-bound form of IL-12 can achieve efficient anti-tumour activity and promote systemic disease targeting via regional T cell delivery in multi-metastatic disease models.
- Eric Hee Jun Lee
- , John P. Murad
- & Saul J. Priceman
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Article
| Open Access
Multi-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1
Mesenchymal stem cells (MSC) are used for immunosuppressive therapy and a uniform source or heterogeneity characterisation is needed. Here the authors use multi-omics to compare human MSC from different sources and ages of donors and show differences in gene expression and immunosuppressive function.
- Yuchen Gao
- , Ying Chi
- & Xiaomin Zhang
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Article
| Open Access
An immunostimulatory glycolipid that blocks SARS-CoV-2, RSV, and influenza infections in vivo
7DW8-5 is a glycolipid that binds CD1d and stimulates invariant natural killer T (iNKT) cells. Here the authors show that 7DW8-5, when administered intranasally, provides prophylactic anti-viral effects against influenza, RSV, and SARS-CoV-2 in mice or hamsters, and that this effect is mediated by iNKT cells and IFN-γ.
- Moriya Tsuji
- , Manoj S. Nair
- & David D. Ho
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Article
| Open Access
Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome
Paediatric acute respiratory distress syndrome (pARDS) is associated with significant mortality and morbidity. Here the authors use single cell sequencing of tracheal aspirate samples from children with pARDS and characterise immune phenotypes and associations with infection stage and pathogen.
- Tim Flerlage
- , Jeremy Chase Crawford
- & Paul G. Thomas
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Article
| Open Access
Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4
IgE antibodies targeting cancer antigens can be used for immunotherapy. Here the authors present an IgE antibody targeting the melanoma-associated antigen, chondroitin sulphate proteoglycan 4, that recognises human melanoma, stimulates tumour cell cytotoxicity, and restricts tumour growth in humanised mouse models.
- Jitesh Chauhan
- , Melanie Grandits
- & Heather J. Bax
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Article
| Open Access
Temperature sensitive liposome based cancer nanomedicine enables tumour lymph node immune microenvironment remodelling
The tumour lymph node microenvironment is an important contributor to the immune suppressiveness of tumours. Here authors target the tumours and the lymph node simultaneously via a pH and photothermal therapy targeted nanoparticle, and show mobilisation of anti-tumour cytotoxic T cells and NK cells and synergistic therapeutic effect with immune checkpoint blockade.
- Shunli Fu
- , Lili Chang
- & Na Zhang
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Article
| Open Access
Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells
The dysfunction of IL-10 secreting regulatory B cells has been linked to the pathogenesis of autoimmune disease. Here the authors show that low dose IL-2 therapy can enhance IL-10 production in regulatory B cell populations via the modulation of BACH2.
- Akimichi Inaba
- , Zewen Kelvin Tuong
- & Menna R. Clatworthy
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Article
| Open Access
Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma
TGF-β stimulated tumor-associated neutrophils (TANs) can exert pro-tumoral functions. Here the authors show that Smad3 activation in TANs is associated with an N2-like polarization state and poor outcome in patients with non-small cell lung carcinoma and that Smad3 targeting reprograms TANs to an antitumor state suppressing tumor growth in preclinical lung cancer models.
- Jeff Yat-Fai Chung
- , Philip Chiu-Tsun Tang
- & Patrick Ming-Kuen Tang
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Article
| Open Access
A comprehensive platform for analyzing longitudinal multi-omics data
The analysis of longitudinal bulk and single-cell multi-omics data is a highly complex task. Here, the authors introduce PALMO, a software platform with five modules to analyse longitudinal bulk and single-cell multi-omics data, which is extensively tested in external datasets that include multiple omics modalities.
- Suhas V. Vasaikar
- , Adam K. Savage
- & Xiao-jun Li
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Article
| Open Access
Citrullination modulates antigen processing and presentation by revealing cryptic epitopes in rheumatoid arthritis
Antibodies directed against citrullinated proteins are commonly found in patients with rheumatoid arthritis. Here, the authors show that citrullination alters the peptide repertoire presented to T cells by altering protease cleavage and inducing protein destabilization, thereby exposing cryptic epitopes.
- Ashley M. Curran
- , Alexander A. Girgis
- & Erika Darrah
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Article
| Open Access
Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation
Myelodysplastic syndromes are characterised by clonal haematopoiesis, with the affected cells often harbouring mutations in the TET2 gene, an important regulator of DNA methylation state. Here authors show that the same mutations are also found in NK cells, perturbing their DNA methylation pattern and cytolytic function.
- Maxime Boy
- , Valeria Bisio
- & Nicolas Dulphy
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Article
| Open Access
G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma
Engineered T cells are used for tumour immunotherapy but can have side effects and need multiple treatment rounds. Here during expansion of T cells from patients, the authors use an inhibitor of the epigenetic regulator G9a/GLP and show that this increases T cell cytotoxic function and tumour reduction in vitro and in vivo respectively.
- Maxine S. Y. Lam
- , Jose Antonio Reales-Calderon
- & Andrea Pavesi
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Article
| Open Access
Enhancing CAR-T cell functionality in a patient-specific manner
‘Manufacturing CAR-T cells is a streamlined and highly regulated procedure involving T-cell-expansion and activation on a standardised platform. Here, the authors show that a personalized approach, taking the phenotypic attributes of individual patients’ T cells into account, leads to more efficient CAR-T cell manufacturing and better CAR-T cell functionality.
- David K. Y. Zhang
- , Kwasi Adu-Berchie
- & David J. Mooney
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Article
| Open Access
Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma
The use of chimeric antigen receptor modified immune cell therapeutics has improved the treatment of a range of tumours. Here the authors explore a dual-target iPSC-derived NK cell product as a potential therapeutic for the treatment of multiple myeloma.
- Frank Cichocki
- , Ryan Bjordahl
- & Jeffrey S. Miller
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Article
| Open Access
Evaluation of cutaneous immune response in a controlled human in vivo model of mosquito bites
Vector-borne pathogens are known to elicit immune response upon mosquito biting the host which is critically linked to the establishment of infection and pathogenesis of disease, yet the impact of the mosquito bite itself is not immunologically well-appreciated. Here the authors characterize the immune response to the mosquito vector Aedes aegypti in a controlled human in vivo challenge model and show the induction of a range of immune pathways and cell types.
- David Guerrero
- , Hoa Thi My Vo
- & Jessica E. Manning
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Article
| Open Access
A phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma
Ad-sig-hMUC1/ecdCD40L is a recombinant adenovirus vaccine comprising human MUC1 antigen fused to the extracellular domain of the CD40 ligand. Here the authors report the result of a phase I clinical trial of Ad-sig-hMUC1/ecdCD40L in patients with advanced adenocarcinoma.
- Tira J. Tan
- , W. X. Gladys Ang
- & Han Chong Toh
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Article
| Open Access
Ex vivo engineered human plasma cells exhibit robust protein secretion and long-term engraftment in vivo
Plasma B cells (PC) are a potential source for protein replacement as they could be engineered to secrete protein other than antibody. Here the authors engineer B cells to express exogenous proteins and demonstrate that these cells can persist long term in adoptive transfer experiments in mice.
- Rene Yu-Hong Cheng
- , King L. Hung
- & Richard G. James
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Article
| Open Access
Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity
Murine models of obesity suggest that decreases in the adipose tissue regulatory T cell compartment may contribute to insulin resistance, but how this corresponds in the human clinical context is less well understood. Here the authors propose a role for interferon gamma in shrinking the adipose tissue regulatory T cell compartment seen in human obesity and assess the alterations seen during induction of dietary changes.
- David Bradley
- , Alan J. Smith
- & Willa A. Hsueh
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Article
| Open Access
Distinct metabolic states guide maturation of inflammatory and tolerogenic dendritic cells
Assessing metabolic activity within single cells rather than at a population level has a number of advantages. Here, the authors use a flow and mass cytometry based approach that assess the metabolic differences between populations of human immune stimulatory and tolerogenic dendritic cells.
- Juraj Adamik
- , Paul V. Munson
- & Lisa H. Butterfield
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Article
| Open Access
Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.
- Yang Chen
- , Keren Jia
- & Lin Shen
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Article
| Open Access
High-dimensional profiling reveals Tc17 cell enrichment in active Crohn’s disease and identifies a potentially targetable signature
The T cell compartment in patients with Crohn's disease is dysregulated. Here the authors use cytometric profiling to reveal an enrichment of distinct Tc17 cells during active Crohn's disease and may suggest CD6 as a potential target for therapeutic studies.
- A.-M. Globig
- , A. V. Hipp
- & B. Bengsch
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Article
| Open Access
Therapeutic efficacy of combined active and passive immunization in ART-suppressed, SHIV-infected rhesus macaques
Antiretroviral therapy alone is insufficient in curing HIV-1 infection, due to latent viral reservoir persistency. Here, authors explore the post-virologic control of combining active and passive immunisation with vesatolimod, in a SHIV-infected rhesus macaque model.
- Victoria E. K. Walker-Sperling
- , Noe B. Mercado
- & Dan H. Barouch
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Article
| Open Access
Low-dose self-amplifying mRNA COVID-19 vaccine drives strong protective immunity in non-human primates against SARS-CoV-2 infection
Self-amplifying mRNA vaccines offer the benefit of driving potent immune responses at low doses, as the mRNA replicates intracellularly. Here, the authors report the preclinical evaluation of a self-amplifying mRNA SARS-CoV-2 vaccine in non-human primates.
- Amy R. Rappaport
- , Sue-Jean Hong
- & Karin Jooss
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Article
| Open Access
A topological refactoring design strategy yields highly stable granulopoietic proteins
Skokowa et al. reconstruct the fold of a granulopoietic cytokine, resulting in de novo, hyperstable, highly active proteins with therapeutic potential for treating several neutropenia disorders.
- Julia Skokowa
- , Birte Hernandez Alvarez
- & Mohammad ElGamacy
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Article
| Open Access
TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease
Reduction of systemic autoimmunity using TNF blockers may also reduce inflammatory diseases in other organs. Here, the authors use a patient database and scRNA-seq to link autoimmune diseases to benign prostatic hyperplasia (BPH), and demonstrate that prostatic hyperplasia is reduced by TNF blockers in humans and mice.
- Renee E. Vickman
- , LaTayia Aaron-Brooks
- & Simon W. Hayward
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Article
| Open Access
Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation
Pannexin-1 ion channels on endothelial cells regulate vascular inflammation and remodeling to mediate aortic aneurysm formation. Pharmacological blockade of Pannexin-1 channels may offer translational therapeutic mitigation of aneurysmal pathology.
- Amanda C. Filiberto
- , Michael D. Spinosa
- & Ashish K. Sharma
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Article
| Open Access
Investigation of Cas9 antibodies in the human eye
Pre-existing antibodies against Cas9 proteins represent a potential issue for gene therapies, including those targeting the eye. Here the authors assess the presence of intraocular antibodies, and show that Cas9 antibodies were prevalent in human serum but not the eye, unless prior bacterial infection occurred.
- Marcus A. Toral
- , Carsten T. Charlesworth
- & Vinit B. Mahajan
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Article
| Open Access
Prognostic tools and candidate drugs based on plasma proteomics of patients with severe COVID-19 complications
Prognostic markers for patients with COVID-19 are of critical importance in determining the course of SARS-CoV-2 infection and patient handling. Here the authors determine and apply a prognostic proteomic panel for risk and drug prediction in the management of SARS-CoV-2 infected patients.
- Maryam A. Y. Al-Nesf
- , Houari B. Abdesselem
- & Fares Al-Ejeh
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Article
| Open Access
Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer
Vaccination with BCG has been shown to induce a pre-priming effect in innate immune cells termed trained immunity. Here the authors re-engineer the BCG vaccine and show augmented immune responses, enhanced induction of trained immunity and improved antitumor efficacy in pre-clinical models of bladder cancer.
- Alok Kumar Singh
- , Monali Praharaj
- & Trinity J. Bivalacqua
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Article
| Open Access
The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression
The advent of immunotherapy has revolutionised cancer therapeutics, but its application in the context of pancreatic ductal adenocarcinoma has been limited. Here authors explore the effect of innate trained responses to fungal β-glucan and assess its effect in a murine model of pancreatic ductal adenocarcinoma where they observe reduced tumour burden and enhanced survival.
- Anne E. Geller
- , Rejeena Shrestha
- & Jun Yan
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Article
| Open Access
Investigating immune and non-immune cell interactions in head and neck tumors by single-cell RNA sequencing
The tumor microenvironment (TME) has an important role in Head and Neck Squamous Cell Carcinoma (HNSCC) progression. Here, using single-cell RNA sequencing and multiplexed imaging, the authors report the cellular complexity of the TME in patients with HNSCC, exploring inflammatory status, stromal heterogeneity and immune checkpoint receptor-ligand interactions.
- Cornelius H. L. Kürten
- , Aditi Kulkarni
- & Robert L. Ferris
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Article
| Open Access
Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients
Strategies to address the challenges associated with product manufacturing can improve chimeric antigen receptor (CAR) cell–based therapeutics. Here the authors report the results of two clinical trials in patients with B-cell malignancies, showing that place-of-care manufacturing has a low production failure rate with CD19-directed CAR-T cell products inducing high remission rates.
- Michael Maschan
- , Paolo F. Caimi
- & Boro Dropulić
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Article
| Open Access
Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex
Facilitated dissociation is a mechanism where antibody-mediated disruption of high-affinity complexes can enhance the therapeutic effects of a drug. Here the authors present a yeast display approach to select and engineer omalizumab variants that dissociate receptor-bound IgE to accelerate its inhibition of the allergic response.
- Luke F. Pennington
- , Pascal Gasser
- & Theodore S. Jardetzky
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Article
| Open Access
Functional convalescent plasma antibodies and pre-infusion titers shape the early severe COVID-19 immune response
Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find CP-mediated, spike/nucleocapsid-focused modulations of humoral responses in the recipient.
- Jonathan D. Herman
- , Chuangqi Wang
- & Galit Alter
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Article
| Open Access
Mesenchymal stromal cell apoptosis is required for their therapeutic function
Mesenchymal stromal cells (MSCs) demonstrate therapeutic benefits in multiple diseases, but the mechanisms remain unclear as infused MSCs do not persist in the body. Here, the authors show that MSC apoptosis is an important mechanistic element, as MSCs rendered genetically incapable of apoptosis lose their ability to ameliorate disease.
- Swee Heng Milon Pang
- , Joshua D’Rozario
- & Tracy S. P. Heng
Phage-specific immunity impairs efficacy of bacteriophage targeting Vancomycin Resistant Enterococcus in a murine model