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| Open AccessA long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity
Chimeric antigen receptor T cells represent a breakthrough treatment in hematologic malignancies, but insufficient level of cytotoxicity and persistence of T cells might compromise success. Authors show here that a recombinant long acting form of interleukin-7 enhances proliferation, persistence and cytotoxicity of the engineered T cells, resulting in long term disease remission.
- Miriam Y. Kim
- , Reyka Jayasinghe
- & John F. DiPersio
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Article
| Open AccessAntigen glycosylation regulates efficacy of CAR T cells targeting CD19
Loss of surface CD19 expression by leukemic cells leads to resistance and relapse to CD19-targeted CAR-T therapies. Here the authors show that loss of SPPL3 in malignant B cells results in hyperglycosylation of CD19.
- Amanda Heard
- , Jack H. Landmann
- & Nathan Singh
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Article
| Open AccessEx vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis
Human regulatory B (Breg) cells have been difficult to study due to their scarcity and heterogeneity. Here the authors expand human B cells to exert immunosuppressive function in vitro and in vivo, and to implicate the TIM-1/STAT3 axis for the regulation of their homoeostasis and function.
- S. Shankar
- , J. Stolp
- & K. J. Wood
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Article
| Open AccessOff-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19
Severe COVID-19 requires immediate and targeted intervention that is efficient against SARS-CoV-2 and its variants. Authors show here the therapeutic potential of engineered natural killer cells that simultaneously express a chimeric antigen receptor targeting the spike protein of SARS-CoV-2, and IL-15, a cytokine that enhances the function and survival of their own.
- Ting Lu
- , Rui Ma
- & Jianhua Yu
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Article
| Open AccessTargeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration
Therapeutic options for non-small cell lung cancer patients with brain metastases are limited. Here the authors design B7-H3 targeting CAR-T cells engineered to express the chemokine receptor CCR2b, and show improved accumulation in the brain and enhanced anti-tumor activity in preclinical models of lung cancer brain metastases.
- Hongxia Li
- , Emily B. Harrison
- & Hongwei Du
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Article
| Open AccessRNA polymerase II pausing factor NELF in CD8+ T cells promotes antitumor immunity
Negative elongation factor B (NELFB) is one of the four subunits of the NELF complex that controls RNA polymerase II pausing. Here the authors show that, by associating with the key T cell transcription factor TCF1, NELFB is required for eliciting CD8 + T cell memory and anti-tumor immune responses.
- Bogang Wu
- , Xiaowen Zhang
- & Rong Li
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Article
| Open AccessUbiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling
The IFNγ response pathway is associated with response to immunotherapy in cancer. Here the authors show that high levels of the IFNγ-receptor (IFNγ-R1) affect the outcome of immunotherapy in a context-dependent fashion and identify the E3 ubiquitin ligase STUB1 as a negative regulator of IFNγ-R1/JAK1 expression in cancer cells.
- Georgi Apriamashvili
- , David W. Vredevoogd
- & Daniel S. Peeper
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Article
| Open AccessSingle-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer
Tumour microenvironment profiling during colorectal cancer progression may enable the discovery of therapeutic targets. Here, single cell and spatial RNA sequencing of tumour and adjacent normal tissues reveals an interaction between FAP+ fibroblasts and SPP1+ macrophages that could be disrupted as an immunotherapy strategy.
- Jingjing Qi
- , Hongxiang Sun
- & Bing Su
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Article
| Open AccessCharacterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma
Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma.
- Nekisa Zakeri
- , Andrew Hall
- & Mala K. Maini
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Article
| Open AccessT-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10
The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness.
- Vidhya M. Ravi
- , Nicolas Neidert
- & Dieter Henrik Heiland
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Article
| Open AccessMesenchymal stem cells transfer mitochondria to allogeneic Tregs in an HLA-dependent manner improving their immunosuppressive activity
Regulatory T (Treg) cells and mesenchymal stem cells (MSCs) are both cell populations capable of immune tolerance induction. Here the authors show that the transfer of mitochondria from mesenchymal stem cells to allogeneic Treg cells in an HLA-dependent manner results in enhanced immunosuppressive functions of Treg cells.
- Karolina Piekarska
- , Zuzanna Urban-Wójciuk
- & Natalia Maria Marek-Trzonkowska
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Article
| Open AccessThe 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 AccessPhagocytosis by an HIV antibody is associated with reduced viremia irrespective of enhanced complement lysis
While antibodies neutralize HIV via Fab recognition of viral surface antigens, antibody Fc domains mediate effector functions, including antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), and complement (C') activity. Here, Spencer et al. modify bNAb 10E8v4 to enhance C'-mediated potency in SHIV challenged rhesus macaques to probe its function in protection, showing that in the absence of neutralization, enhancing C' activities in vitro adds no value toward reducing viremia in either blood or tissue.
- David A. Spencer
- , Benjamin S. Goldberg
- & Ann J. Hessell
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Article
| Open AccessCAR T cells redirected to cell surface GRP78 display robust anti-acute myeloid leukemia activity and do not target hematopoietic progenitor cells
There is an unmet need to discover suitable targets for CAR-T therapy in patients with acute myeloid leukemia (AML). Here the authors show that GRP78, a key regulator of the unfolded protein response, is highly expressed on the surface of primary AML blasts, but not on normal lymphocytes and hematopoietic progenitor cells, and that GRP78-CAR T have anti-AML activity in preclinical models.
- Nikhil Hebbar
- , Rebecca Epperly
- & M. Paulina Velasquez
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Article
| Open AccessGPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models
Immunologically cold tumours don’t respond to immune checkpoint blockade inhibition due to poor recruitment of anti-tumour T cells. Authors show here that melanoma-associated lymphatic endothelial cells express G Protein-Coupled Receptor 182 that scavenges CXCL9 and other chemokines necessary for T cell recruitment.
- Robert J. Torphy
- , Yi Sun
- & Yuwen Zhu
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Article
| Open AccessNeoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma
Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. .
- Joris L. Vos
- , Joris B. W. Elbers
- & Charlotte L. Zuur
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Article
| Open AccessCD137 (4-1BB) costimulation of CD8+ T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation
Costimulation has been shown to be required for optimal activation of T cells and it could be delivered either in trans with respect to the source of CD3-TCR ligation or in cis on the same cell. Here the authors show that CD137 costimulation is more effective when delivered in cis to enhance T cell proliferation and activation.
- Itziar Otano
- , Arantza Azpilikueta
- & Ignacio Melero
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Article
| Open AccessBiomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy
Antibodies targeting OX40 or CD137, two T cell costimulatory receptors, have been shown to improve antitumor immunity. Here the authors design a phospholipid-derived nanoparticle to deliver OX40 or CD137 mRNA to T cells in vivo, improving efficacy of anti-OX40 and anti-CD137 antibody therapy in preclinical tumor models.
- Wenqing Li
- , Xinfu Zhang
- & Yizhou Dong
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Article
| Open AccessDepletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab
Elimination of regulatory T cells via the anti-CCR4 monoclonal antibody, mogamulizumab, is expected to augment anti-tumour immune response. Authors show here that although regulatory T cell targeting is successful, clinical improvement remains minimal in patients with solid tumours due to concomitant and unintended depletion of central memory CD8+ T cells.
- Yuka Maeda
- , Hisashi Wada
- & Hiroyoshi Nishikawa
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Article
| Open AccessMesenchymal 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
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Article
| Open AccessRegulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation
TGFβ is secreted in an inactive form in the tumor microenvironment. Authors here show that although TGFβ is produced mainly by cancer cells, regulatory T cells are necessary for its activation via expression of the b8 chain of avb8 integrin. Thus, both cell types contribute to TGFβ dependent tumor growth.
- Alexandra Lainé
- , Ossama Labiad
- & Julien C. Marie
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Article
| Open AccessCOVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models
Monoclonal antibodies show great promise in treating Covid-19 patients. Here, Maisonnasse, Aldon and colleagues report pre-clinical results for COVA1-18 and demonstrate that it reduces viral infectivity in three animal models with over 95% efficacy in macaques upper respiratory tract.
- Pauline Maisonnasse
- , Yoann Aldon
- & Roger Le Grand
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Article
| Open AccessPhase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis
Leptomeningeal metastases from solid tumors are a rare complication with a very poor prognosis. Here the authors report the efficacy and safety of combined ipilimumab and nivolumab in patients with leptomeningeal carcinomatosis.
- Priscilla K. Brastianos
- , Matthew R. Strickland
- & Ryan J. Sullivan
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Article
| Open AccessAn oncolytic virus expressing a full-length antibody enhances antitumor innate immune response to glioblastoma
Oncolytic herpes simplex virus-1 lyses cancer cells while increases their immunogenicity. Blocking the CD47 “don’t eat me” signal on cancer cells promotes their phagocytosis by macrophages. Authors here show that oncolytic viruses expressing anti-CD47 antibodies improve glioblastoma survival in mouse models.
- Bo Xu
- , Lei Tian
- & Jianhua Yu
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Article
| Open AccessC3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates
Donor-specific antibodies in sensitized recipients may cause kidney transplant rejection. Here the authors show that complement component C3 inhibition prolongs graft survival by inhibiting T and B cell proliferation/activation and hence tissue injury, despite antibody levels remaining unaffected.
- Robin Schmitz
- , Zachary W. Fitch
- & Stuart J. Knechtle
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Article
| Open AccessA modular self-adjuvanting cancer vaccine combined with an oncolytic vaccine induces potent antitumor immunity
Successful cancer immune therapy correlates with a T cell-inflamed tumour microenvironment. Authors show here that co-administration of a self-adjuvanting protein vaccine and an antigen-expressing oncolytic virus in an optimised regimen strongly enhances T cell immunogenicity and may turn non-inflamed tumours proinflammatory and less resistant to checkpoint blockade therapy.
- Krishna Das
- , Elodie Belnoue
- & Guido Wollmann
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Article
| Open AccessPan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity
Although circulating tumour DNA (ctDNA) can predict immune checkpoint blockade (ICB) responses, its association with tumour biomarkers remains unknown. Here, the authors use ctDNA to inform exome and transcriptome profiling of >100 patients with 30 cancer types on a single clinical ICB trial and identify tumour microenvironment features associated with response.
- S. Y. Cindy Yang
- , Scott C. Lien
- & Trevor J. Pugh
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Article
| Open AccessTumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape
The immunocytokine NHS-IL12 is targeted to necrotic tumour areas to prompt an immune response. Authors show here in mouse colon and breast models that the combination of histone deacetylase inhibitor, Entinostat, and NHS-IL12 generates a tumour microenvironment that favours tumour resolution.
- Kristin C. Hicks
- , Paul L. Chariou
- & Sofia R. Gameiro
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Article
| Open AccessNodal immune flare mimics nodal disease progression following neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer
Granulomatous/sarcoid-like lesions have been reported in patients treated with immune checkpoint inhibitors (ICIs). Here the authors report the occurrence of “nodal immune flare”, an apparent radiological cancer progression in the nodes characterized by the absence of cancer and the presence of non-caseating granulomas, in patients with non-small cell lung cancer following neoadjuvant ICI treatment.
- Tina Cascone
- , Annikka Weissferdt
- & Boris Sepesi
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Article
| Open AccessMortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors
Regional differences in SARS-CoV-2 variants may affect treatment outcome. Here, the authors show that near-sourced convalescent plasma has higher efficacy, as defined by death within 30 days of transfusion, than plasma sourced more than 150 miles away.
- Katie L. Kunze
- , Patrick W. Johnson
- & Michael J. Joyner
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Article
| Open AccessA human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade
The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.
- Cecile Geuijen
- , Paul Tacken
- & Mark Throsby
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Article
| Open AccessFrancisella tularensis induces Th1 like MAIT cells conferring protection against systemic and local infection
Mucosal-Associated Invariant T (MAIT) cells are associated with established functions during bacterial infection. Here the authors show inoculation with Francisella tularensis results in induction of MAIT cells associated with prototypic Th1 immunity and confer protection to systemic and local infection.
- Zhe Zhao
- , Huimeng Wang
- & Zhenjun Chen
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Matters Arising
| Open AccessInconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets
- Xu Xiao
- , Canqiang Xu
- & Rongshan Yu
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Article
| Open AccessIrreversible electroporation augments checkpoint immunotherapy in prostate cancer and promotes tumor antigen-specific tissue-resident memory CD8+ T cells
Irreversible electroporation (IRE), a soft-tissue ablation technique used for tumour ablation, has been suggested to promote systemic immune responses. Here the authors show that IRE, followed by anti-CTLA-4 blockade, elicits the expansion of tumor antigen-specific CD8+ T cells and is associated with tissue residency and improved anti-tumor immune response in a preclinical model of prostate cancer.
- Brandon J. Burbach
- , Stephen D. O’Flanagan
- & Yoji Shimizu
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Article
| Open AccessGenetic variation associated with thyroid autoimmunity shapes the systemic immune response to PD-1 checkpoint blockade
Endocrinopathies, such as thyroid autoimmunity, are common among patients treated with immune checkpoint inhibitors. Here, by using a polygenic risk score (PRS) derived from a hypothyroidism GWAS, the authors show that cancer patients with high PRS are at increased risk of atezolizumab (anti-PD-L1)-induced thyroid dysfunction, a condition associated with systemic response to PD-1 checkpoint blockade and longer overall survival.
- Zia Khan
- , Christian Hammer
- & G. Scott Chandler
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Article
| Open AccessAn antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage
Mechanisms underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin treatment during anticancer therapy remain poorly understood. Here the authors show that treatment with an antibody against the L1 cell adhesion molecule inhibits nuclear L1CAM translocation, thereby controlling vascular DNA damage and preventing cardiotoxicity.
- Jae-Kyung Nam
- , A-Ram Kim
- & Yoon-Jin Lee
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Article
| Open AccessCRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy
Activation of the adenosine receptor A2AR is associated with suppression of T cell function in the tumor microenvironment. To overcome immunosuppression, here the authors show that CRISPR/Cas9 mediated deletion of A2AR enhances CAR T cell effector functions without altering memory or persistence properties, improving CAR-T mediated tumor control in pre-clinical models.
- Lauren Giuffrida
- , Kevin Sek
- & Paul A. Beavis
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Article
| Open AccessPLGA-particle vaccine carrying TLR3/RIG-I ligand Riboxxim synergizes with immune checkpoint blockade for effective anti-cancer immunotherapy
PLGA based cancer immunotherapy incorporating antigen and TLR ligands has resulted in enhancement of the anti-tumour response. Here, the authors explore the use of a defined double stranded RNA adjuvant, Riboxxim, and test its incorporation with PLGA immunotherapy in the context of in vivo tumour models and show enhanced induction of the anti-tumour response.
- Julia Koerner
- , Dennis Horvath
- & Marcus Groettrup
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Article
| Open AccessIL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques
Infection of African green monkeys with SIV is associated with reduced pathogenicity. Here the authors explore the requirement of differentiated NK cell populations in a pathogenic Rhesus macaque model of SIV infection and show administration of IL-21 and IFNα rescues terminally differentiated NK cells, similarly to what found in African green monkeys, and limits the SIV reservoir in antiretroviral therapy treated macaques.
- Justin Harper
- , Nicolas Huot
- & Mirko Paiardini
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Article
| Open AccessA cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy
While recognized as the first effective immunotherapy for human cancer, IL-2 based immunotherapy still encounters several limitations in the clinic. Here, the authors design a cytokine receptor-masked IL-2 mutein prodrug that is selectively activated by matrix metalloproteinases in the tumor microenvironment, promoting anti-tumor immune response while minimizing systemic toxicity.
- Eric J. Hsu
- , Xuezhi Cao
- & Yang-Xin Fu
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Article
| Open AccessFUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer
B7H3 is a transmembrane B7 family checkpoint molecule present on many cancer cells. Here the authors show that FUT8 mediates fucosylation of B7H3 to limit the immune response to triple-negative breast cancer as a potentially targeted mechanism of non-responsiveness to current checkpoint therapies.
- Yun Huang
- , Hai-Liang Zhang
- & Rong Deng
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Article
| Open AccessThe survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5
Regulatory B (Breg) cells suppress excessive inflammation primary via the production of interleukin 10 (IL-10). Here the authors show that the function and homeostasis of mouse and human IL-10+ Breg cells are negatively regulated by the cell surface receptor, SLAMF5, to impact experimental autoimmunity, thereby hinting SLAMF5 as a potential target for immunotherapy.
- Lihi Radomir
- , Matthias P. Kramer
- & Idit Shachar
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Article
| Open AccessViral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling
Innate intratumoral immunity might be important in enhancing oncolytic tumor immunotherapy. Here, the authors show that recombinant poliovirus signalling through TBK-IRF3 enhances tumor-infiltrating T cell activity and multi-cytokine function.
- Michael C. Brown
- , Mubeen M. Mosaheb
- & Matthias Gromeier
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Article
| Open AccessCirculating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy
Immune checkpoint inhibition (ICI) shows potential for cancer therapies, but response rates vary. Here, the authors use single-cell analyses to show that, in a 28 patient cohort, patients stratified by mucosal-associated invariant T (MAIT) percentages show different response rates, and ICI responders have more MAIT cells expressing CXCR4 and granzyme B.
- Sara De Biasi
- , Lara Gibellini
- & Andrea Cossarizza
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Article
| Open AccessIdentification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma
There is an unmet clinical need to identify therapeutic options for the treatment of pancreatic cancer (PDAC). Here the authors present a systematic screening approach for the identification of potential PDAC cell surface target candidates for CAR-T cell based immunotherapy, followed by their functional validation in preclinical models.
- Daniel Schäfer
- , Stefan Tomiuk
- & Olaf Hardt
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Article
| Open AccessVirus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis
Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4+ effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.
- James A. Hutchinson
- , Katharina Kronenberg
- & Sebastian Haferkamp
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Article
| Open AccessT-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors
There is an urgent need to discover blood-based biomarkers to predict response to immune checkpoint inhibitors (ICI). Here the authors show that effective ICI therapy correlates with increased frequency of circulating CX3CR1+CD8+ T cells in preclinical tumor models and in a cohort of patients with non-small cell lung cancer treated with anti-PD-1.
- Takayoshi Yamauchi
- , Toshifumi Hoki
- & Fumito Ito
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Article
| Open AccessStructures of mouse and human GITR–GITRL complexes reveal unique TNF superfamily interactions
Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and GITR ligand (GITRL) regulate immune cell activities, including anti-tumor immune responses. Structures and visualization of human and mouse GITR–GITRL complexes offer insight into the architecture of higher-order membrane assemblies, and their signaling.
- Feng Wang
- , Bryant Chau
- & Pavel Strop
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Article
| Open AccessCheckpoint inhibition through small molecule-induced internalization of programmed death-ligand 1
Programmed death-ligand 1 (PD-L1) is involved in the inhibition of antigen specific T cells via ligation of programmed death 1 (PD-1). Here, the authors show checkpoint inhibition by use of small molecule inhibition of PD-L1 which in a humanised mouse model was shown to restore T cell responses and reduced tumour burden.
- Jang-June Park
- , Emily P. Thi
- & Chris B. Moore