Showing papers in "Journal of Experimental Medicine in 2020"
The Feinstein Institute for Medical Research1, Cold Spring Harbor Laboratory2, Cornell University3, Hofstra University4, McGill University5, University of Michigan6, University of California, San Francisco7, University of Texas MD Anderson Cancer Center8, McGill University Health Centre9, University of Utah10
TL;DR: Autopsy results and literature are presented supporting the hypothesis that neutrophil extracellular traps (NETs) may contribute to organ damage and mortality in COVID-19, and existing drugs that target NETs, although unspecific, may benefit CO VID-19 patients.
Abstract: Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
1,138 citations
TL;DR: It is described that SARS-CoV-2 triggers the release of ACE2-depended neutrophil extracellular traps (NETs) that mediate lung pathology, supporting the use of NETs inhibitors for COVID-19 treatment.
Abstract: Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.
624 citations
TL;DR: Pseudotyped HIV-1– and vesicular stomatitis virus–based reporter viruses and a replication-competent vesicle stom atitis virus/SARS-CoV-2 chimera represent useful tools to assess neutralizing antibodies.
Abstract: The emergence of SARS-CoV-2 and the ensuing explosive epidemic of COVID-19 disease has generated a need for assays to rapidly and conveniently measure the antiviral activity of SARS-CoV-2-specific antibodies. Here, we describe a collection of approaches based on SARS-CoV-2 spike-pseudotyped, single-cycle, replication-defective human immunodeficiency virus type-1 (HIV-1), and vesicular stomatitis virus (VSV), as well as a replication-competent VSV/SARS-CoV-2 chimeric virus. While each surrogate virus exhibited subtle differences in the sensitivity with which neutralizing activity was detected, the neutralizing activity of both convalescent plasma and human monoclonal antibodies measured using each virus correlated quantitatively with neutralizing activity measured using an authentic SARS-CoV-2 neutralization assay. The assays described herein are adaptable to high throughput and are useful tools in the evaluation of serologic immunity conferred by vaccination or prior SARS-CoV-2 infection, as well as the potency of convalescent plasma or human monoclonal antibodies.
448 citations
TL;DR: This Perspective explores the contributions of the innate and adaptive immune systems to both viral control as well as toxicity during COVID-19 infections and offers suggestions to both understand and therapeutically modulate anti-COVID immunity.
Abstract: The novel 2019 strain of coronavirus is a source of profound morbidity and mortality worldwide. Compared with recent viral outbreaks, COVID-19 infection has a relatively high mortality rate, the reasons for which are not entirely clear. Furthermore, treatment options for COVID-19 infection are currently limited. In this Perspective, we explore the contributions of the innate and adaptive immune systems to both viral control as well as toxicity during COVID-19 infections and offer suggestions to both understand and therapeutically modulate anti-COVID immunity.
434 citations
TL;DR: The role of TGF-β in tissue fibrosis is discussed, highlighting the mechanisms of T GF-β activation and signaling, the cellular targets of TDF-β actions, and the challenges of therapeutic translation.
Abstract: TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β-driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.
367 citations
TL;DR: The authors review the molecular mechanisms regulatingIL-10 production and response and describe classic and novel functions of IL-10 in immune and non-immune cells.
Abstract: The cytokine IL-10 is a key anti-inflammatory mediator ensuring protection of a host from over-exuberant responses to pathogens and microbiota, while playing important roles in other settings as sterile wound healing, autoimmunity, cancer, and homeostasis. Here we discuss our current understanding of the regulation of IL-10 production and of the molecular pathways associated with IL-10 responses. In addition to IL-10's classic inhibitory effects on myeloid cells, we also describe the nonclassic roles attributed to this pleiotropic cytokine, including how IL-10 regulates basic processes of neural and adipose cells and how it promotes CD8 T cell activation, as well as epithelial repair. We further discuss its therapeutic potential in the context of different diseases and the outstanding questions that may help develop an effective application of IL-10 in diverse clinical settings.
301 citations
TL;DR: This review discusses current knowledge of the blood–brain barrier, emphasizing key unanswered questions.
Abstract: The blood vessels vascularizing the central nervous system exhibit a series of distinct properties that tightly control the movement of ions, molecules, and cells between the blood and the parenchyma. This "blood-brain barrier" is initiated during angiogenesis via signals from the surrounding neural environment, and its integrity remains vital for homeostasis and neural protection throughout life. Blood-brain barrier dysfunction contributes to pathology in a range of neurological conditions including multiple sclerosis, stroke, and epilepsy, and has also been implicated in neurodegenerative diseases such as Alzheimer's disease. This review will discuss current knowledge and key unanswered questions regarding the blood-brain barrier in health and disease.
295 citations
TL;DR: It is shown that AAV-mediated expression of human ACE2 allows for SARS-CoV-2 infection and disease investigation in mice and this pathology is in part driven by type I interferon signaling.
Abstract: Severe acute respiratory syndrome-coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus's inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.
288 citations
TL;DR: Neutrophil extracellular traps infiltrate the airway, interstitial, and vascular compartments, supporting the hypothesis that they may drive several aspects of COVID-19 lung pathology and represent therapeutic targets.
Abstract: Infection with SARS-CoV-2 is causing a deadly and pandemic disease called coronavirus disease-19 (COVID-19). While SARS-CoV-2-triggered hyperinflammatory tissue-damaging and immunothrombotic responses are thought to be major causes of respiratory failure and death, how they relate to lung immunopathological changes remains unclear. Neutrophil extracellular traps (NETs) can contribute to inflammation-associated lung damage, thrombosis, and fibrosis. However, whether NETs infiltrate particular compartments in severe COVID-19 lungs remains to be clarified. Here we analyzed postmortem lung specimens from four patients who succumbed to COVID-19 and four patients who died from a COVID-19-unrelated cause. We report the presence of NETs in the lungs of each COVID-19 patient. NETs were found in the airway compartment and neutrophil-rich inflammatory areas of the interstitium, while NET-prone primed neutrophils were present in arteriolar microthrombi. Our results support the hypothesis that NETs may represent drivers of severe pulmonary complications of COVID-19 and suggest that NET-targeting approaches could be considered for the treatment of uncontrolled tissue-damaging and thrombotic responses in COVID-19.
247 citations
TL;DR: Results support p-tau-217 is superior to p- tau-181 as an AD plasma biomarker as well as demonstrating plasma tau phosphorylation measures are increased with amyloid.
Abstract: Highly sensitive and specific plasma biomarkers for Alzheimer's disease (AD) have the potential to improve diagnostic accuracy in the clinic and facilitate research studies including enrollment in prevention and treatment trials. We recently reported CSF tau hyperphosphorylation, especially on T217, is an accurate predictor of β-amyloidosis at asymptomatic and symptomatic stages. In the current study, we determine by mass spectrometry the potential utility of plasma p-tau isoforms to detect AD pathology and investigate CSF and plasma tau isoforms' profile relationships. Plasma tau was truncated as previously described in CSF. CSF and plasma measures of p-tau-217 and p-tau-181 were correlated. No correlation was found between CSF and plasma on total-tau levels and pS202 measures. We found p-tau-217 and p-tau-181 were highly specific for amyloid plaque pathology in the discovery cohort (n = 36, AUROC = 0.99 and 0.98 respectively). In the validation cohort (n = 92), p-tau-217 measures were still specific to amyloid status (AUROC = 0.92), and p-tau-181 measures were less specific (AUROC = 0.75).
210 citations
TL;DR: Chan and Schroder review inflammasome signaling and cell death decisions, mechanisms underpinning IL-1α,IL-1β, IL-18, and IL-37 maturation and release, and the functions of these cytokines in protective and pathological inflammation.
Abstract: Specific IL-1 family cytokines are expressed by cells as cytosolic pro-forms that require cleavage for their activity and cellular release. IL-1β, IL-18, and IL-37 maturation and secretion is governed by inflammatory caspases within signaling platforms called inflammasomes. By inducing pyroptosis, inflammasomes can also drive the release of the alarmin IL-1α. Recent advances have transformed our mechanistic understanding of inflammasome signaling, cell death decisions, and cytokine activation and secretion. Here, we provide an updated view of inflammasome signaling; mechanisms underpinning IL-1α, IL-1β, IL-18, and IL-37 maturation and release; and the functions of these cytokines in protective and pathological inflammation.
TL;DR: Single-cell transcriptome analysis of epithelial cells from human ileum, colon, and rectum reveals different nutrient-absorption preferences in the small and large intestine, providing a rich resource for further characterization of human intestine cell constitution and functions.
Abstract: The intestine plays an important role in nutrient digestion and absorption, microbe defense, and hormone secretion. Although major cell types have been identified in the mouse intestinal epithelium, cell type-specific markers and functional assignments are largely unavailable for human intestine. Here, our single-cell RNA-seq analyses of 14,537 epithelial cells from human ileum, colon, and rectum reveal different nutrient absorption preferences in the small and large intestine, suggest the existence of Paneth-like cells in the large intestine, and identify potential new marker genes for human transient-amplifying cells and goblet cells. We have validated some of these insights by quantitative PCR, immunofluorescence, and functional analyses. Furthermore, we show both common and differential features of the cellular landscapes between the human and mouse ilea. Therefore, our data provide the basis for detailed characterization of human intestine cell constitution and functions, which would be helpful for a better understanding of human intestine disorders, such as inflammatory bowel disease and intestinal tumorigenesis.
TL;DR: It is demonstrated that a mAb specific for the human microglial receptor TREM2 induces microglia proliferation, ameliorates Aβ-induced pathology in a mouse model of Alzheimer’s disease, and can be given safely in a first-in-human phase I clinical trial.
Abstract: TREM2 is a receptor for lipids expressed in microglia The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology Thus, AD may benefit from TREM2 activation Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2 Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers We conclude that AL002 is a promising candidate for AD therapy
TL;DR: The Viewpoint discusses the benefits and potential limitations of using interferon lambda (IFN-λ, a type III interferons) to prevent, limit, and treat COVID-19.
Abstract: With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.
TL;DR: IL-22 is a pleiotropic cytokine that acts in the regulation of host defense, barrier function, and metabolism and is focused on its physiological role in mucosal tissues in health and disease.
Abstract: The cytokine interleukin-22 (IL-22) is a critical regulator of epithelial homeostasis. It has been implicated in multiple aspects of epithelial barrier function, including regulation of epithelial cell growth and permeability, production of mucus and antimicrobial proteins (AMPs), and complement production. In this review, we focus specifically on the role of IL-22 in the intestinal epithelium. We summarize recent advances in our understanding of how IL-22 regulates homeostasis and host defense, and we discuss the IL-22 pathway as a therapeutic target in diseases of the intestine, including inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), and cancer.
TL;DR: IL17 cross-talk with pancreatic cancer cells orchestrates neutrophil recruitment and activation of Padi4-dependent NETosis, resulting in immune spatial remodeling and immunosuppression reversal.
Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
TL;DR: This study reviews the literature on the biology of GM-CSF, in particular that describing the research leading to clinical trials targeting GM- CSF and its receptor in numerous inflammatory/autoimmune conditions, such as rheumatoid arthritis.
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells. Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology. Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions. Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis. This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.
TL;DR: A unique subset of CD163+ Tim4+ tissue-resident macrophages in omentum that are maintained independently of bone marrow–derived monocytes and have a specific role in the metastatic spread of ovarian cancer cells are identified.
Abstract: Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny and function of TAM subsets in a mouse model of metastatic ovarian cancer that is representative for visceral peritoneal metastasis. We show that the omentum is a critical premetastatic niche for development of invasive disease in this model and define a unique subset of CD163+ Tim4+ resident omental macrophages responsible for metastatic spread of ovarian cancer cells. Transcriptomic analysis showed that resident CD163+ Tim4+ omental macrophages were phenotypically distinct and maintained their resident identity during tumor growth. Selective depletion of CD163+ Tim4+ macrophages in omentum using genetic and pharmacological tools prevented tumor progression and metastatic spread of disease. These studies describe a specific role for tissue-resident macrophages in the invasive progression of metastatic ovarian cancer. The molecular pathways of cross-talk between tissue-resident macrophages and disseminated cancer cells may represent new targets to prevent metastasis and disease recurrence.
TL;DR: A model of pathogen-induced priming and inhibition of TAK1 is used to demonstrate RIPK1 kinase activity–independent inflammasome activation and pyroptosis, apoptosis, and necroptosis that drive myeloid proliferation and sepsis in TAK 1-deficient animals.
Abstract: RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity-independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity-independent cell death complex to drive pyroptosis and apoptosis. Furthermore, we found fully functional RIPK1 kinase activity-independent necroptosis driven by the RIPK3-MLKL pathway in TAK1-deficient macrophages. In vivo, TAK1 inactivation resulted in RIPK3-caspase-8 signaling axis-driven myeloid proliferation and a severe sepsis-like syndrome. Overall, our study highlights a previously unknown mechanism for RIPK1 kinase activity-independent inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) that could be targeted for treatment of TAK1-associated myeloid proliferation and sepsis.
TL;DR: This study reveals that some commensal gut microbiota accumulate inside the distal tumor microenvironment and facilitate CD47 blockade–mediated immunity in a STING- and interferon-dependent fashion.
Abstract: Most studies focus on how intestinal microbiota influence cancer immunotherapy through activating gut immunity. However, immunotherapies related to innate responses such as CD47 blockade rely on the rapid immune responses within the tumor microenvironment. Using one defined anaerobic gut microbiota to track whether microbiota interact with host immunity, we observed that Bifidobacterium facilitates local anti-CD47 immunotherapy on tumor tissues through the capacity to accumulate within the tumor microenvironment. Systemic administration of Bifidobacterium leads to its accumulation within the tumor and converts the nonresponder mice into responders to anti-CD47 immunotherapy in a stimulator of interferon genes (STING)- and interferon-dependent fashion. Local delivery of Bifidobacterium potently stimulates STING signaling and increases cross-priming of dendritic cells after anti-CD47 treatment. Our study identifies the mechanism by which gut microbiota preferentially colonize in tumor sites and facilitate immunotherapy via STING signaling.
TL;DR: This study reveals profound alteration in biology of blood unconventional T cells (MAIT, iNKT, and γδT) in severe COVID-19, and activation levels of MAIT/iNKT cells at admission positively correlate with clinical improvement.
Abstract: COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19-driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS-CoV-2-driven ARDS.
TL;DR: This review discusses the molecular mechanism of IL-6 expression and how this knowledge leads to the clinical field, and presents an overview of the complex biology of interleukin-6 family cytokines.
Abstract: Interleukin-6 (IL-6) has been identified as a 26-kD secreted protein that stimulates B cells to produce antibodies. Later, IL-6 was revealed to have various functions that overlap with other IL-6 family cytokines and use the common IL-6 signal transducer gp130. IL-6 stimulates cells through multiple pathways, using both membrane and soluble IL-6 receptors. As indicated by the expanding market for IL-6 inhibitors, it has become a primary therapeutic target among IL-6 family cytokines. Here, we revisit the discovery of IL-6; discuss insights regarding the roles of this family of cytokines; and highlight recent advances in our understanding of regulation of IL-6 expression.
TL;DR: Susan Weiss discusses the milestones of the coronavirus field and future perspectives on SARS-CoV-2 research.
Abstract: I have been researching coronaviruses for more than forty years. This viewpoint summarizes some of the major findings in coronavirus research made before the SARS epidemic and how they inform current research on the newly emerged SARS-CoV-2.
French Institute of Health and Medical Research1, University of Edinburgh2, Manchester Academic Health Science Centre3, Pasteur Institute4, University of Oxford5, University of Paris6, university of lille7, Royal Hospital for Sick Children8, Paris Descartes University9, Necker-Enfants Malades Hospital10
TL;DR: Heterozygous missense mutations in COPA underlie constitutive interferon signaling through STING, thereby defining a novel type I interfer onopathy and emphasizing the importance of the ER–Golgi axis in interferons homeostasis.
Abstract: Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
TL;DR: This work has shown that metabolic reprogramming through enforced very-long-chain acyl-CoA dehydrogenase expression enhances intratumor T cells survival and persistence in pancreatic tumor microenvironment, overcoming a major hurdle to immunotherapy for PDA.
Abstract: CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.
TL;DR: This review discusses the growing literature on the pathogenic role of IL-17 in cancer, focusing on recent studies that placeIL-17 as a nexus linking inflammation, tissue repair, and cancer.
Abstract: IL-17, a potent proinflammatory cytokine, has been shown to intimately contribute to the formation, growth, and metastasis of a wide range of malignancies. Recent studies implicate IL-17 as a link among inflammation, wound healing, and cancer. While IL-17-mediated production of inflammatory mediators mobilizes immune-suppressive and angiogenic myeloid cells, emerging studies reveal that IL-17 can directly act on tissue stem cells to promote tissue repair and tumorigenesis. Here, we review the pleotropic impacts of IL-17 on cancer biology, focusing how IL-17-mediated inflammatory response and mitogenic signaling are exploited to equip its cancer-promoting function and discussing the implications in therapies.
TL;DR: Using murine models and human samples, the authors show that progressive glomerulosclerosis results from loss of decay-accelerating factor (DAF/CD55) on podocytes, which in turn initiates complement C3aR signaling and downstream IL-1β/IL-1R1–mediated podocyte injury and loss.
Abstract: Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β-induced podocyte injury, potentially identifying new therapeutic targets.
TL;DR: It is demonstrated that lncRNA-encoded polypeptide ASRPS is down-regulated in TNBC and may serve as a novel prognostic marker and therapeutic target for TNBC.
Abstract: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with the most aggressive phenotype and poor overall survival. Using bioinformatics tools, we identified LINC00908 encoding a 60-aa polypeptide and differentially expressed in TNBC tissues. We named this endogenously expressed polypeptide ASRPS (a small regulatory peptide of STAT3). ASRPS expression was down-regulated in TNBCs and associated with poor overall survival. We showed that LINC00908 was directly regulated by ERα, which was responsible for the differential down-regulation of LINC00908 in TNBCs. ASRPS directly bound to STAT3 through the coiled coil domain (CCD) and down-regulated STAT3 phosphorylation, which led to reduced expression of VEGF. In human endothelial cells, a mouse xenograft breast cancer model, and a mouse spontaneous BC model, ASRPS expression reduced angiogenesis. In a mouse xenograft breast cancer model, down-regulation of ASRPS promoted tumor growth, and ASRPS acted as an antitumor peptide. We presented strong evidence that LINC00908-encoded polypeptide ASRPS represented a TNBC-specific target for treatment.
TL;DR: The role of galectins in shaping cellular circuitries governing each hallmark of tumors is dissected, illustrating relevant examples and highlighting novel opportunities for treating human cancer.
Abstract: Hanahan and Weinberg have proposed 10 organizing principles that enable growth and metastatic dissemination of cancer cells. These distinctive and complementary capabilities, defined as the "hallmarks of cancer," include the ability of tumor cells and their microenvironment to sustain proliferative signaling, evade growth suppressors, resist cell death, promote replicative immortality, induce angiogenesis, support invasion and metastasis, reprogram energy metabolism, induce genomic instability and inflammation, and trigger evasion of immune responses. These common features are hierarchically regulated through different mechanisms, including those involving glycosylation-dependent programs that influence the biological and clinical impact of each hallmark. Galectins, an evolutionarily conserved family of glycan-binding proteins, have broad influence in tumor progression by rewiring intracellular and extracellular circuits either in cancer or stromal cells, including immune cells, endothelial cells, and fibroblasts. In this review, we dissect the role of galectins in shaping cellular circuitries governing each hallmark of tumors, illustrating relevant examples and highlighting novel opportunities for treating human cancer.
TL;DR: Type III IFNs, or IFN-λ, are the latest addition to the IFN family thanks to a restricted pattern of expression of their receptor and to unique immunomodulatory properties, which stimulates pathogen clearance while curbing inflammation to maintain barrier integrity.
Abstract: Type III IFNs, or IFN-λ, are the newest members of the IFN family and were long believed to play roles that were redundant with those of type I IFNs. However, IFN-λ displays unique traits that delineate them as primary protectors of barrier integrity at mucosal sites. This unique role stems both from the restricted expression of IFN-λ receptor, confined to epithelial cells and to a limited pool of immune cells, and from unique immunomodulatory properties of IFN-λ. Here, we discuss recent findings that establish the unique capacity of IFN-λ to act at the barriers of the host to balance tissue tolerance and immune resistance against viral and bacterial challenges.