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| Open AccessTumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
Here authors show that GDF15, a cytokine that is produced by cancer cells, prevents T cells from extravasation into the tumour microenvironment. Low availability of T cells in GDF-15-expressing tumours thus precludes effective immune therapy.
- Markus Haake
- , Beatrice Haack
- & Jörg Wischhusen
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Article
| Open AccessA randomized non-inferiority trial of therapeutic strategy with immunosuppressants versus biologics for Vogt-Koyanagi-Harada disease
Different classes of biologic therapeutics have been assessed in the context of Vogt-Koyanagi-Harada disease. Here the authors compared cyclosporine immunosuppression or adalimumab in a randomised clinical trial for the treatment of patients with Vogt-Koyanagi-Harada disease and found non-inferiority upon treatment with cyclosporine.
- Zhenyu Zhong
- , Lingyu Dai
- & Peizeng Yang
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| Open AccessNanovesicles loaded with a TGF-β receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy
Targeting the TGF-β signaling pathway has been exploited to relieve immunosuppression in the tumor microenvironment. Here the authors describe the design of a nanoplatform integrating the TGF-β receptor 1 inhibitor LY2157299 and the ROS-responsive JQ1 pro-drug, promoting anti-tumor immune responses in preclinical cancer models.
- Mengxue Zhou
- , Jiaxin Wang
- & Haijun Yu
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| Open AccessAdoptive T cell transfer and host antigen-presenting cell recruitment with cryogel scaffolds promotes long-term protection against solid tumors
Adoptive T cell therapy has shown remarkable promise for the treatment of haematological malignancies. Here, the authors show that a cryogel platform for the simultaneous delivery of autologous T cells and recruitment of local antigen-presenting cells promotes long-lasting responses against solid tumours in mice.
- Kwasi Adu-Berchie
- , Joshua M. Brockman
- & David J. Mooney
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| Open AccessNeoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors
Tumor neoantigens versus tumor-associated antigens may have different functions in antitumor immunity depending on the strength of antigen recognition. Here the authors characterize CD8 T cell clones specific for TAA, neoantigens or viral antigens isolated from tumor and blood and show that neoantigen-specific clones have a higher structural avidity than TAA-specific ones and preferentially infiltrate tumors.
- Julien Schmidt
- , Johanna Chiffelle
- & Alexandre Harari
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| Open AccessIn vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer
There is still a limited understanding of mechanisms of sensitivity/resistance to cancer immunotherapy. Here the authors perform in vivo CRISPR/Cas9 loss-of-function screens in mouse lung cancer models, revealing Serpinb9 and Adam2 as regulators of immunotherapy response.
- Dzana Dervovic
- , Ahmad A. Malik
- & Daniel Schramek
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Article
| Open AccessGas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation
Gas-based therapy is an emerging therapeutic option for cancer treatment. Here the authors design a virus-mimicking hollow mesoporous tetrasulfide-doped organosilica for co-encapsulation of an aggregation-induced emission (AIE)-active luminogen and manganese carbonyl to fabricate a STING activating gas nano-adjuvant for photo-immunotherapy, promoting anti-tumor immune response in preclinical models.
- Kaiyuan Wang
- , Yang Li
- & Xiaoyuan Chen
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Article
| Open AccessPost-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting
Chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors are promising platforms for cell-based immunotherapies. Here, the authors develop highly programmable versions of these receptors that can be universally targeted to antigens of interest through covalent enzyme chemistry.
- Elisa Ruffo
- , Adam A. Butchy
- & Jason Lohmueller
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Article
| Open AccessIdentification of CircRNA signature associated with tumor immune infiltration to predict therapeutic efficacy of immunotherapy
Circular RNAs are known to be linked to cancer regulation. Here, the authors identify a circular RNA signature associated with immune checkpoint response in melanoma.
- Yu Dong
- , Qian Gao
- & Youqiong Ye
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Article
| Open AccessTemperature 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 AccessLow-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 AccessImmunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer’s disease
Acid sphingomyelinase (ASM) is a sphingolipid metabolizing enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide, and previous work has shown it is upregulated in models of Alzheimer’s disease. Here the authors demonstrate in a mouse model of Alzheimer’s disease that antibody-based immunotherapy targeting plasma ASM resulted in attenuated neuropathological features by suppressing pathogenic Th17 cells.
- Byung Jo Choi
- , Min Hee Park
- & Jae-sung Bae
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Article
| Open AccessSTING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma
Glioblastoma is an immunologically cold tumour, with poor CD8 + T cell infiltration and enrichment in immunosuppressive tumour-associated myeloid cells. Here, the authors generate a bispecific lipid nanoparticle targeting CD47 and PD-L1, combined with a STING agonist, to promote anti-tumour immunity.
- Peng Zhang
- , Aida Rashidi
- & Maciej S. Lesniak
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Article
| Open AccessClonal dynamics of alloreactive T cells in kidney allograft rejection after anti-PD-1 therapy
Immune checkpoint inhibitors (ICI) may have unanticipated side effects in transplant recipients who subsequently develop tumors. Here the authors used single-cell sequencing to identify and characterize allogeneic reactive T cells that developed after an ICI course for melanoma in a transplant recipient.
- Garrett S. Dunlap
- , Daniel DiToro
- & Deepak A. Rao
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| Open AccessT cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles
Glioblastoma is a highly aggressive, and also the most common, brain tumour type in adults. Here, the authors generate a nanoparticle encapsulating the TLR7/8 agonist, R848, which induces tumour regression in mice by reprogramming myeloid cells independently of T and NK cells.
- Verena Turco
- , Kira Pfleiderer
- & Michael Platten
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Article
| Open AccessDeletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy
The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.
- Marcel P. Trefny
- , Nicole Kirchhammer
- & Alfred Zippelius
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Article
| Open AccessG9a/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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| Open AccessReprogramming systemic and local immune function to empower immunotherapy against glioblastoma
Glioblastoma (GBM) is characterized by local and systemic immunosuppression, showing limited responses to immunotherapies. Here the authors describe the design of a nanoplatform composed of the lymphopenia alleviating agent cannabidiol and the lymphocyte recruiting cytokine LIGHT, promoting anti-tumor immune responses in GBM preclinical models.
- Songlei Zhou
- , Yukun Huang
- & Jun Chen
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| Open AccessQuadruple 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 AccessInflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer
Inflammatory conditions often affect colorectal cancer patients, and their effect on their ongoing treatment is a pressing medical question. Here authors show that inflammation interferes with local anti-tumour immune response and inhibits response to immune checkpoint blockade therapy via immunosuppressive neutrophil leukocytes.
- Qiaoqi Sui
- , Xi Zhang
- & Pei-Rong Ding
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| Open AccessPromoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation
Cancer cells exploit immune checkpoint pathways, such as PD-1/PD-L1, to evade elimination by the immune system. Here, the authors demonstrate that TMUB1 regulates post-translational modifications of PD-L1 and that targeting the TMUB1/PD-L1 interaction promotes anti-tumour T cells responses
- Chengyu Shi
- , Ying Wang
- & Aifu Lin
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Article
| Open AccessCostimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity
The blockade of CD28 signalling is known to reduce pathological T cell responses in the context of both autoimmunity and transplantation, but has been associated with impairment of the regulatory T cell compartment. Here the authors show combining costimulation blockade with the administration of interleukin 2 selectively impairs the T effector response whilst maintaining the regulatory T cell pool and suggest functional effect in a murine model of autoimmune diabetes.
- Chun Jing Wang
- , Lina Petersone
- & Lucy S. K. Walker
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Article
| Open AccessCDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
Inducing phagocytic capacities of tumour-associated macrophages to eliminate cancer cells is a promising immunotherapy. Here, the authors show that engineered macrophages overexpressing CDKN1A/p21 reduce leukaemic tumour burden and increase survival in preclinical mouse models of human T-ALL.
- Awatef Allouch
- , Laurent Voisin
- & Jean-Luc Perfettini
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| Open AccessCD8+ T cell differentiation status correlates with the feasibility of sustained unresponsiveness following oral immunotherapy
Oral immunotherapy (OIT) clinical trials have helped a subset of participants achieve sustained unresponsiveness (SU) to the cognate allergen. Here the authors analyse immune cells from participants from one peanut OIT trial and show that CD8+ T cell differentiation status at baseline may help to predict the likelihood of achieving SU.
- Abhinav Kaushik
- , Diane Dunham
- & Kari C. Nadeau
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| Open AccessAnalysis of anti-SARS-CoV-2 Omicron-neutralizing antibody titers in different vaccinated and unvaccinated convalescent plasma sources
Although COVID-19 convalescent plasma is commonly used for the treatment of immunosuppressed patients, this approach has yielded mixed results. Here, the authors present a systematic review of Omicron-neutralization data in convalescent plasma from vaccinated and unvaccinated individuals.
- David J. Sullivan
- , Massimo Franchini
- & Daniele Focosi
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| Open AccessNeuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma
Responses to immune checkpoint blockade (ICB) in patients with glioblastoma are limited. Here the authors show that Calmodulin-Dependent Kinase Kinase 2 (CaMKK2) is expressed in tumor associated macrophages and neurons and is associated with resistance to ICB in preclinical models of glioblastoma.
- William H. Tomaszewski
- , Jessica Waibl-Polania
- & John H. Sampson
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| Open AccessA 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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| Open AccessTargeting vasoactive intestinal peptide-mediated signaling enhances response to immune checkpoint therapy in pancreatic ductal adenocarcinoma
Poor antitumor response of pancreatic cancer to immunotherapies is a major barrier to effective disease management. Herein we show that pancreatic cancers overexpress vasoactive intestinal peptide, and pharmacological inhibition of its signaling significantly enhances responsiveness of pancreatic ductal adenocarcinoma to immune checkpoint therapy, thus improving overall survival in mouse models.
- Sruthi Ravindranathan
- , Tenzin Passang
- & Edmund K. Waller
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| Open AccessEnhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response
Activation of ESCRT-mediated cell membrane repair can reduce the extent of tumor cell pyroptosis. Here the authors develop two formulations (an injectable hydrogel and a cell patch) for the sustained release of a Gasdermin-D bacteria-based delivery system and of biodegradable nanoparticles loaded with an ESCRT inhibitor, triggering pyroptosis and antitumor immune responses in preclinical cancer models.
- Zhaoting Li
- , Fanyi Mo
- & Quanyin Hu
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Article
| Open AccessMetabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion
Chemo-resistance and immune evasion are major challenges in osteosarcoma treatment. Here the authors show that doxorubicin promotes IL-18 secretion by tumor associated macrophages inducing LAT2-dependent CD47 upregulation in osteosarcoma cells, suggesting LAT2 inhibition as a therapeutic option in combination with doxorubicin.
- Zenan Wang
- , Binghao Li
- & Zhaoming Ye
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Article
| Open AccessCo-expression of a PD-L1-specific chimeric switch receptor augments the efficacy and persistence of CAR T cells via the CD70-CD27 axis
Co-expression of PD-L1-specific chimeric switch receptors (CSRs) improves the antitumor effects of chimeric antigen receptor (CAR) T cells. Here, CSRs are shown to promote the differentiation of mesothelin-targeting CAR T cells into central memory-like cells and improve their efficacy.
- Le Qin
- , Yuanbin Cui
- & Peng Li
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Article
| Open AccessTGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine
TGF-β has been shown to regulate stem-like CD8 + T cell differentiation into tissue resident memory T cells in chronic infection. Here authors show that in tumour-bearing mice, a similar TGF-βdependent CD8 + T cell differentiation program is carried out in the draining lymph nodes, which impedes generation of anti-tumor migratory effector T cells upon future vaccination.
- Guo Li
- , Saranya Srinivasan
- & Nu Zhang
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| Open AccessEvolution and modulation of antigen-specific T cell responses in melanoma patients
Previous studies have characterized the diversity and dynamics of the T cell receptor (TCR) repertoire in patients with solid cancer. Here, by analyzing TCR repertoire data from multiple datasets, the authors report that melanoma-associated antigen-specific TCRs can be used to separate metastatic melanoma patients from healthy controls and to follow anti-tumor responses in patients treated with immunotherapy.
- Jani Huuhtanen
- , Liang Chen
- & Satu Mustjoki
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| Open AccessDevelopment of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer
The development of neutralizing antibodies can limit the therapeutic effectiveness of systemically administered oncolytic viruses (OV). Here, to enable repeated intravenous administration, the authors report the development of synthetic RNA viruses formulated within lipid nanoparticles, showing anti-tumor efficacy even in the presence of OV neutralizing antibodies.
- Edward M. Kennedy
- , Agnieszka Denslow
- & Lorena Lerner
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Article
| Open AccessDNA-delivered antibody cocktail exhibits improved pharmacokinetics and confers prophylactic protection against SARS-CoV-2
Here, Parzych et al describe the development of a DNA-delivered SARS-CoV-2 mAb cocktail displaying synergistic RBD binding that confers broad neutralizing activity against variants of concern and prophylactic efficacy in multiple small animal models.
- Elizabeth M. Parzych
- , Jianqiu Du
- & David B. Weiner
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Article
| Open AccessA protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses
Manganese has a crucial role in cGAS-STING-mediated DNA sensing and has emerged as a STING agonist. Here the authors report the design and characterization of a nanosystem incorporating manganese ions and the chemotherapeutic drug β-lapachone, inducing T-cell mediated anti-tumor immune responses in preclinical cancer models.
- Xuan Wang
- , Yingqi Liu
- & Zhong Luo
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Article
| Open AccessA pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma
In patients with locally advanced resectable oral squamous cell carcinoma (OSCC), the risk of recurrence and metastasis following treatment is high. Here, a phase I clinical trial reports safety and pathological response of neoadjuvant camrelizumab and apatinib in patients with locally advanced resectable OSCC.
- Wu-tong Ju
- , Rong-hui Xia
- & Lai-ping Zhong
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Article
| Open AccessTherapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen
Cancers often harbor mutations in genes encoding important regulatory proteins, but therapeutic targeting of these molecules proves difficult due to their high structural similarity to their non-mutated counterpart. Here authors show the engineering of T cell engaging bispecific protein able to selectively target cancer cells with a high-frequency mutation in the KRAS oncogene.
- Andrew Poole
- , Vijaykumar Karuppiah
- & Chandramouli Chillakuri
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Article
| Open AccessCAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies
The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.
- Yongxian Hu
- , Jingjing Li
- & He Huang
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Article
| Open AccessLactate increases stemness of CD8 + T cells to augment anti-tumor immunity
Lactic acid from glycolytic metabolism of cancer cells has been associated with immune suppressive functions. Here authors show that lactate, when depart from the acidic protons, inhibits histone deacetylases in CD8 + T cells, which turns them into potent anti-tumour immune cells.
- Qiang Feng
- , Zhida Liu
- & Jinming Gao
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Article
| Open AccessNoninvasive imaging of the tumor immune microenvironment correlates with response to immunotherapy in gastric cancer
Tumour microenvironment has been linked with immunotherapy response in gastric cancer. Here, the authors use CT-based radiomics to predict neutrophils-to-lymphocyte ratio and response to immunotherapy.
- Weicai Huang
- , Yuming Jiang
- & Guoxin Li
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Article
| Open AccessMultifunctional nanoparticle potentiates the in situ vaccination effect of radiation therapy and enhances response to immune checkpoint blockade
Radiotherapy can activate an in situ vaccine response and promote response to immune checkpoint inhibitors. Here the authors design a multifunctional nanoparticle to enhance tumor antigen presentation and modulate the tumor immune microenvironment following radiotherapy, showing improved anti-tumor immune responses in radiotherapy-treated tumors when combined with immune checkpoint inhibitors.
- Ying Zhang
- , Raghava N. Sriramaneni
- & Zachary S. Morris
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Article
| Open AccessTemporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice
Immune checkpoint blockade (ICB) is partially successful as a cancer therapy. Here using mouse models, the authors transcriptionally monitor responding and non-responding tumours showing that responding tumours were associated with transient IFN-β signalling which could promote the anti-tumour response.
- Rachael M. Zemek
- , Wee Loong Chin
- & W. Joost Lesterhuis
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Article
| Open AccessInorganic nanosheets facilitate humoral immunity against medical implant infections by modulating immune co-stimulatory pathways
Bacterial biofilm formation is a major risk of surgical implantation, and necessitates implant removal and aggressive antibiotic treatment. Here authors show that post-surgical application of Manganese-containing inorganic nanosheets reduces residual and recurrent infection by improving antigen presentation and humoral immune response against the biofilms.
- Chuang Yang
- , Yao Luo
- & Xianlong Zhang
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Article
| Open AccessPromotion of neutralizing antibody-independent immunity to wild-type and SARS-CoV-2 variants of concern using an RBD-Nucleocapsid fusion protein
Protection against SARS-CoV-2 infection involves T cell and B cell responses but only studying one or the other has proved difficult. Here the authors immunise with a fusion protein construct of N and RBD proteins from SARS-CoV-2 and find that this promotes protection in animal models preferentially via T cells.
- Julia T. Castro
- , Patrick Azevedo
- & Ricardo T. Gazzinelli
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Article
| Open AccessCancer immune therapy using engineered ‛tail-flipping’ nanoliposomes targeting alternatively activated macrophages
Tumor-associated macrophages are mostly pro-tumorigenic, due to their re-programming by the tumor microenvironment. Here authors show that nanoliposomes, incorporating phospholipids with a flipping-tail chain, are engulfed specifically by intratumoral, alternatively activated macrophages, while delivering a cargo that converts these cells into anti-tumor macrophages.
- Praneeth R. Kuninty
- , Karin Binnemars-Postma
- & Jai Prakash
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Article
| Open AccessSpatiotemporal control of engineered bacteria to express interferon-γ by focused ultrasound for tumor immunotherapy
Several approaches have been recently proposed to engineer bacteria for cancer immunotherapy. Here the authors design an ultrasound-responsive bacterium for the controlled release of IFNy at the tumor site, promoting anti-tumor immune responses in preclinical models.
- Yuhao Chen
- , Meng Du
- & Fei Yan
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Article
| Open AccessStructures of the T cell potassium channel Kv1.3 with immunoglobulin modulators
The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune responses. Here, the authors report structures of the Kv1.3 potassium channel with and without immunoglobulin modulators, shedding light on the mechanisms of Kv1.3 gating and modulation.
- Purushotham Selvakumar
- , Ana I. Fernández-Mariño
- & Joel R. Meyerson
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Article
| Open AccessCD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas
Understanding CD8 + T cell response to immune checkpoint blockade at the molecular level is important for the design of more efficient cancer immune therapies. Authors show here that the histone lysine methyltransferase Suv39h1 controls the transcriptional programs that determine the functionality of CD8 + T cells and Suv39h1 inhibition may potentiate anti-PD-1 therapy of melanomas.
- Leticia Laura Niborski
- , Paul Gueguen
- & Eliane Piaggio