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| Open AccessSuppressive IL-17A+Foxp3+ and ex-Th17 IL-17AnegFoxp3+ Treg cells are a source of tumour-associated Treg cells
Th17 cells can transdifferentiate into regulatory T (Treg) cells. Here the authors characterize tumour-driven Th17-to-Tregcell transdifferentiation and identify potential cancer therapy targets.
- Stephanie Downs-Canner
- , Sara Berkey
- & Nataša Obermajer
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Article
| Open AccessThe Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression
Tyrosine kinase signalling in cancer cells promotes immune evasion. Here, the authors show that tyrosine kinases engage scaffold protein Shc1 to promote immunosuppression in breast cancer by simultaneously activating STAT3 immunosuppressive signals and impairing STAT1-driven anti-tumour immune responses.
- Ryuhjin Ahn
- , Valérie Sabourin
- & Josie Ursini-Siegel
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Article
| Open AccessSmad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development
Smad3, a transcription factor activated by TGF-β, has been implicated in tumorigenesis. Here the authors show that Smad3 inhibits NK cell differentiation and effector function by repressing NFIL3, and that genetic or pharmacological blockade of Smad3 expands tumour-suppressive NK cells and restricts tumour growth in mice.
- Patrick Ming-Kuen Tang
- , Shuang Zhou
- & Hui-Yao Lan
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Article
| Open AccessSpatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression
Viruses are promising anti-tumour therapeutics due to induction of an immune response and/or oncolytic activity. Here, Kalkavanet al. show that LCMV replicates in tumour cells, without inducing cell lysis, and that its anti-tumour activity is largely mediated by recruitment of interferon-producing monocytes.
- Halime Kalkavan
- , Piyush Sharma
- & Karl S. Lang
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Article
| Open AccessIFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting
T cell mediated anti-tumour immune responses result in the emergence of an immune-resistant population in a process called immunoediting. Here, the authors show that immunoediting is associated with an increase in genomic rearrangements of tumour cells that requires both cytotoxic T cells and IFNγ exposure.
- Kazuyoshi Takeda
- , Masafumi Nakayama
- & Mark J. Smyth
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Article
| Open AccessTumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice
PD-L1, the ligand for T-cell inhibitory receptor PD-1, can be expressed by various cell types in the tumour microenvironment. Here, the authors show that, in mouse models, the expression of PD-L1 from both cancerous and normal host immune cells is important for suppressing anti-tumour immune responses.
- Janet Lau
- , Jeanne Cheung
- & Maike Schmidt
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Article
| Open AccessHeterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging
Tumour-associated macrophages (TAM) can be used as prognostic indicators in cancer. Here, the authors establish a platform for high-throughput 3D microscopy in murine lung carcinoma that allows to visualize TAMs infiltration throughout the entire lung, response to CSF-1R blockade and nanoparticle drug delivery.
- Michael F. Cuccarese
- , J. Matthew Dubach
- & Ralph Weissleder
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Article
| Open AccessNeutrophils dominate the immune cell composition in non-small cell lung cancer
Tumour immune evasion can involve multiple strategies. Here, the authors characterize the immune populations from clinical specimens of lung cancer in conjunction with TCR-β sequencing and show abundant neutrophils affecting cytotoxic T-cell content and the frequent presence of tumour-specific T-cell clones.
- Julia Kargl
- , Stephanie E. Busch
- & A. McGarry Houghton
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Article
| Open AccessThe immunoreceptor NKG2D promotes tumour growth in a model of hepatocellular carcinoma
Expression of NKG2D immunoreceptor ligands on tumour cells is believed to inhibit tumour growth through engaging NKG2D-expressing immune cells. Here, the authors show that in a model of liver cancer the NKG2D/NKG2D-ligand pathway can also promote tumour formation by sustaining an inflammatory environment.
- Sam Sheppard
- , Joana Guedes
- & Nadia Guerra
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Article
| Open AccessThe tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity
Dendritic cells are antigen-presenting cells consisting of distinct subsets originating from different lineages. Here, the authors identify the subsets of dendritic cells populating the tumour tissue in both mice and humans and find they have opposing functions in regulating the anti-tumour immune response.
- Damya Laoui
- , Jiri Keirsse
- & Jo A. Van Ginderachter
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Article
| Open AccessReprogramming the immunological microenvironment through radiation and targeting Axl
Radiotherapy can enhance the antitumour immune response. Here, the authors show that resistance to radiation in breast cancer cells can be due to Axl expression that suppresses antigen presentation though MHCI, promotes NF-κB signalling, and enhances cytokine release promoting a suppressive myeloid microenvironment.
- Todd A. Aguilera
- , Marjan Rafat
- & Amato J. Giaccia
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Article
| Open AccessTemporal stability and molecular persistence of the bone marrow plasma cell antibody repertoire
Longevity of antibody responses has been attributed to persistence of plasma cells in mice. Here the authors provide human data in support of this model by immunoglobulin sequencing bone marrow sections from two human donors over 6.5 years to show temporal stability of plasma cell clonotypes, but not other B cells.
- Gabriel C. Wu
- , Nai-Kong V. Cheung
- & Gregory C. Ippolito
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Article
| Open AccessSoluble IL-33 receptor sST2 inhibits colorectal cancer malignant growth by modifying the tumour microenvironment
IL-33 is a pro-inflammatory cytokine with a role in colorectal cancer. Here, the authors show that circulating tumour-derived sST2, an IL-33 decoy receptor, delayed the growth and progression of colorectal cancer cells by inhibiting Th1/Th2 polarization, macrophage infiltration and angiogenesis.
- Miho Akimoto
- , Riruke Maruyama
- & Keizo Takenaga
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Article
| Open AccessDirect identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry
Neoantigens determine anti-cancer immunoreactivity and are important functional targets for immunotherapy. Here, the authors use deep mass spectrometry to characterize neoepitopes from human melanoma tissue and show the presence of tumour-reactive T cells with specificity for selected neoantigens.
- Michal Bassani-Sternberg
- , Eva Bräunlein
- & Angela M. Krackhardt
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Article
| Open AccessDendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma
Activation and biological function of B cells in cancer are still unclear. Here, the authors show that hepatocarcinoma cells drive the formation of semimature dendritic cells that in turn activate FcγRIIlow/−tumour B cells through the CD95L/CD95 axis, leading to the production of IL-10 and suppression of CD8 T cells.
- Fang-Zhu Ouyang
- , Rui-Qi Wu
- & Dong-Ming Kuang
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Article
| Open AccessSaponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation
Saponin-based adjuvants are being explored as vaccine components as they induce high levels of antigen cross-presentation, but it is unknown how. Here the authors show that these adjuvants enhance cross-presentation by driving production of lipid bodies inside CD11b dendritic cells.
- Martijn H. den Brok
- , Christian Büll
- & Gosse J. Adema
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Article
| Open AccessCancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers
A reactive tumour stroma is associated with poor prognosis. Here, the authors show that in patients with triple negative breast cancer resident monocytes activate cancer-associated fibroblasts and induce production of CXCL16, which acts as a monocyte chemoattractant, resulting in an amplificatory feedback loop.
- Roni Allaoui
- , Caroline Bergenfelz
- & Karin Leandersson
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Article
| Open AccessObesity-associated NLRC4 inflammasome activation drives breast cancer progression
Obesity is associated with higher breast cancer risk and poor prognosis. Here, the authors show that obesity promotes breast cancer through the recruitment of macrophages with activated NLRC4 inflammasome, which activate IL-1β production, resulting in VEGFA expression in adipocytes and angiogenesis.
- Ryan Kolb
- , Liem Phan
- & Weizhou Zhang
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Article
| Open AccessSelective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy
High-affinity IL-2Rα expressed by Tregs mitigates the potential of IL-2 use in cancer therapy. Here, the authors fuse IL-2 with an NKDG2 binding domain, and show that it induces IL-2 signalling selectively in NKG2D+cells, delaying tumour growth in mice without the side effects of conventional IL-2 therapy.
- Reza Ghasemi
- , Eric Lazear
- & Alexander Sasha Krupnick
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Article
| Open AccessGlycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity
Programmed Death ligand-1 (PD-L1) protein mediates immune suppression in cancer. Here, the authors show that in breast cancer, PD-L1 expression can be up regulated post-translationally by glycosylation, which in turn acts through inhibiting GSK3β-mediated PD-L1 degradation.
- Chia-Wei Li
- , Seung-Oe Lim
- & Mien-Chie Hung
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Article
| Open AccessTargeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia
Chemerin is an adipokine often downregulated in tumours. Here the authors show that chemotherapy induces chemerin production by endothelial cells, leading to cachexia, and that VEGF ablation in myeloid cells prevents cachexia in a chemerin-dependent manner, and improves chemotherapeutic effects.
- Ralph Klose
- , Ewelina Krzywinska
- & Christian Stockmann
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Article
| Open AccessInterdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy
Combination therapy with α-CTLA-4 and α-PD-1 is showing improved therapeutic effects in clinical trials. Here, the authors report that mechanistically in bladder cancer such effect depends upon an upregulation of T cell activity mediated by the IL-7/IL-7R and IFN-γ/IFN-γR signalling pathways.
- Lewis Zhichang Shi
- , Tihui Fu
- & Padmanee Sharma
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Article
| Open AccessDectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells
Dendritic cells instruct different types of T cell responses depending on the types of microbial ligands sensed. Here the authors show that dendritic cells stimulated via Dectin-1 receptor upregulate TNFSF15 and OX40L and induce T helper 9 response and efficient antitumour immunity in mouse models.
- Yinghua Zhao
- , Xiao Chu
- & Siqing Wang
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Article
| Open AccessCD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity
CAR-T targeting CD19 have been successfully used in a variety of B-cell malignancies but patients may eventually relapse. Here, the authors show that CD19 CAR-T resistance in pre-B cell ALL can be due to the induction of a myeloid lineage switch through an epigenetic alterations in master regulators of B cell development.
- Elad Jacoby
- , Sang M. Nguyen
- & Terry J. Fry
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Article
| Open AccessA major secretory defect of tumour-infiltrating T lymphocytes due to galectin impairing LFA-1-mediated synapse completion
Galectin-3 is a sugar-binding protein that can inhibit antitumour cytotoxic immunity. Here the authors show that Galectin-3 expressed by tumour cells inhibits LFA-1 on cytotoxic lymphocytes, impairing immunological synapse formation, IFNg secretion, and target cell killing.
- Anne-Elisabeth Petit
- , Nathalie Demotte
- & Pierre van der Bruggen
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Article
| Open AccessDecreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
JAK inhibitors are currently undergoing evaluation in clinical trials for advanced breast cancer. Here, the authors show that JAK pathway inhibition increases metastasis in mouse models of breast cancer by impairing NK anti-tumour activity and that these side effects can be overcome by addition of IL-15.
- Alessia Bottos
- , Dagmar Gotthardt
- & Nancy E. Hynes
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Review Article
| Open AccessRecommendations for myeloid-derived suppressor cell nomenclature and characterization standards
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population expanded in cancer and other chronic inflammatory conditions. Here the authors identify the challenges and propose a set of minimal reporting guidelines for mouse and human MDSC.
- Vincenzo Bronte
- , Sven Brandau
- & Dmitry I. Gabrilovich
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Article
| Open AccessHomeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
The homeobox NKX2 family of transcriptional factors has been shown to regulate fundamental developmental processes. Here, the authors show that NKX2-3 is a bona fideoncogenic driver in marginal-zone B-cell lymphoma and that it promotes lymphomagenesis by shaping lymphocyte dynamics and promoting BCR signalling.
- Eloy F. Robles
- , Maria Mena-Varas
- & Jose A. Martinez-Climent
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Article
| Open AccessThe PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages
Elevated IL-33 levels have been correlated with metastasis and poor prognosis. Here the authors show in mouse tumour xenograft models that PDGF-BB produced by tumour cells induces IL-33 via Sox7 in tumour pericytes, and IL-33 promotes metastasis through its effects on tumour-associated macrophages.
- Yunlong Yang
- , Patrik Andersson
- & Yihai Cao
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Article
| Open AccessC1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation
C1q is known to initiate the activation of the complement classical pathway. Here, the authors show the C1q is expressed in the tumour microenvironment and can promote cancer cell migration and adhesion in a complement activation-independent manner.
- Roberta Bulla
- , Claudio Tripodo
- & Francesco Tedesco
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Article
| Open AccessIntegrative analysis of breast cancer reveals prognostic haematopoietic activity and patient-specific immune response profiles
Tumour samples are heterogeneous and are comprised of multiple cell types in addition to cancer cells. Here, the authors devised a method to estimate the relative levels of haematopoietic cells in breast cancer samples and demonstrate that this correlates with prognosis.
- Frederick S. Varn
- , Erik H. Andrews
- & Chao Cheng
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Article
| Open AccessBAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages
BAG3 is found in the serum of pancreatic cancer patients and can be used as a marker of disease, but its role in cancer is unclear. Here, the authors show that BAG3 secreted from tumour cells binds to and activates macrophages, which in turn promotes cell growth, and an antibody blocking BAG3 binding reduces tumour formation in mice.
- Alessandra Rosati
- , Anna Basile
- & Maria Caterina Turco
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Article |
Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity
The presence of lymph node-like vasculature in tumours correlates with positive prognosis, but the mechanisms by which it forms and affects tumour growth are unclear. Here the authors show that it is induced by CD8 and NK cells, and supports naive T cells’ differentiation into antitumour effectors.
- J. David Peske
- , Elizabeth D. Thompson
- & Victor H. Engelhard
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Article
| Open AccessId1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation
Tumour progression is promoted by the generation of an immunosuppressive macroenvironment. Here, the authors demonstrate that the Inhibitor of Differentiation 1 promotes the switch from dendritic cell differentiation towards myeloid-derived suppressor cell expansion during tumour progression.
- Marianna Papaspyridonos
- , Irina Matei
- & David Lyden
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Article |
The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity
ABCG1 transporter pumps cholesterol out of the cell. Here, the authors show that ABCG1-deficient mice have reduced tumour growth due to a switch of the tumour-associated macrophages from a tumour-promoting to tumour-suppressing phenotype, and are protected from the pro-tumorigenic effects of a Western-like diet.
- Duygu Sag
- , Caglar Cekic
- & Catherine C. Hedrick
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Article |
The Wilms’ tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression
The Wilms’ tumour suppressor Wt1 is highly expressed in vessels and stromal cells of human tumours, but not in adjacent healthy tissue. Here the authors show that Wt1 regulates Pecam-1 and c-kitand that deletion of Wt1 in endothelial, haematopoietic and myeloid suppressor cells leads to tumour regression.
- Kay-Dietrich Wagner
- , Julien Cherfils-Vicini
- & Nicole Wagner
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Article |
SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells
The underlying molecular mechanisms that mediate natural killer (NK) cell tuning remain unclear. Here, the authors show that SHP-1 is essential for the function of MHC class I-specific inhibitory receptors and for setting the threshold of NK cell reactivity.
- Charlotte Viant
- , Aurore Fenis
- & Eric Vivier
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Article |
Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression
Tumour-infiltrating lymphocytes (TILs) can be suppressed by the tumour, but how this occurs is not clear. Here the authors show that the miR-200 family, which suppresses epithelial–mesenchymal transition, also targets tumour cell PD-L1 and thereby intratumoral immunosuppression and metastasis.
- Limo Chen
- , Don L. Gibbons
- & F. Xiao-Feng Qin
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Article |
Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ
Dendritic cells (DC) are known to promote cancer progression by suppressing antitumor immunity. Here, Rehm et al. describe a mechanism whereby lymphoma cells induce C/EBPβ activation in DCs, which in turn secrete cytokines that support the proliferation and survival of lymphoma cells.
- Armin Rehm
- , Marcel Gätjen
- & Uta E. Höpken
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Article |
TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
TNF-α signalling regulates a range of pathophysiological functions including tumour growth, but its role in lymphatic metastasis is unclear. Here the authors show that TNF-α signalling stimulates lymphatic endothelial cell activity, lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.
- Hong Ji
- , Renhai Cao
- & Yihai Cao
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Article |
Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia
Ca2+signalling pathways are known to influence T-cell development and T-cell leukemia progression. Here the authors show that deletion of all three inositol triphosphate receptor homologues in mice severely impairs T-cell development in the thymus and causes spontaneous T-cell acute lymphoblastic leukemia.
- Kunfu Ouyang
- , Rafael Leandro Gomez-Amaro
- & Ju Chen
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Article |
p38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression
Dendritic cell-based approaches to induce antitumour immunity are promising, but have not shown encouraging results in clinical trials. Here the authors show that inhibition of p38 MAPK in dendritic cells increases expression of OX40L, boosting antitumour T-cell responses and dampening regulatory T-cell activity.
- Yong Lu
- , Mingjun Zhang
- & Qing Yi
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Article |
Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4
The Ras oncogene has many different roles in cancer including the production of cytokines that can influence the tumour microenvironment. Here, Catanzaro et al.demonstrate that Ras can modulate the expression of SerpinB3/B4, which leads to increased cytokine production and tumour growth.
- Joseph M. Catanzaro
- , Namratha Sheshadri
- & Wei-Xing Zong
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Article |
slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells
slanDCs represent a population of dendritic cells whose role in cancer immune surveillance is not known. Here, the authors reveal that in cancer patients, slanDCs accumulate in the metastatic tumour-draining lymph nodes but not primary carcinoma sites, suggesting their involvement in nodal immune responses to cancer cells.
- William Vermi
- , Alessandra Micheletti
- & Marco A. Cassatella
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Article
| Open AccessPrimary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci
Tumours are thought to pave the way for metastases to distant organs by secreting factors create regions of increased vascular permeability. Hiratsuka et al.identify innate immune pathways that underlie this process in the pre-metastatic lungs of tumour-bearing mice and patients.
- Sachie Hiratsuka
- , Sachie Ishibashi
- & Yoshiro Maru
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Article |
A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer
The tumour microenvironment is often found to be immunosuppressive. Reppert and colleagues show that human and murine lung tumours harbour IL-17A-producing T cells, and that blocking IL-17A increases survival in mice, suggesting that anti-IL-17A therapy may be useful in treating lung cancer.
- S. Reppert
- , I. Boross
- & S. Finotto