Showing 1 - 12 of 28 results for "19853"
- ReferenceC. Zhang et al. (jan 2020) Cell metabolism 31 1 148--161.e5
STAT3 Activation-Induced Fatty Acid Oxidation in CD8+ T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth.
Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8+ T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8+ T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8+ T cells activates STAT3 to increase FAO, inhibiting CD8+ T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8+ T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8+ T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis. View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceA. Mansurov et al. ( 2020) Nature biomedical engineering 4 5 531--543
Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours.
Checkpoint-inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in 'immunologically cold' tumours has been modest. Interleukin-12 (IL-12) is a powerful cytokine that activates the innate and adaptive arms of the immune system; however, the administration of IL-12 has been associated with immune-related adverse events. Here we show that, after intravenous administration of a collagen-binding domain fused to IL-12 (CBD-IL-12) in mice bearing aggressive mouse tumours, CBD-IL-12 accumulates in the tumour stroma due to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD-IL-12 induced sustained intratumoural levels of interferon-$\gamma$, substantially reduced its systemic levels as well as organ damage and provided superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD-IL-12 potently synergized with CPI to eradicate large established melanomas, induced antigen-specific immunological memory and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD-IL-12 may potentiate CPI immunotherapy for immunologically cold tumours. View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceW. Wang et al. (may 2019) Nature 569 7755 270--274
CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy.
Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNgamma) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNgamma expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNgamma and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach. View PublicationCatalog #: Product Name: 17953 EasySep™ Human CD8+ T Cell Isolation Kit 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 17953 Product Name: EasySep™ Human CD8+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceK. E. Sivick et al. (dec 2018) Cell reports 25 11 3074--3085.e5
Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity.
Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFalpha is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity. View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceY. Nakanishi et al. (dec 2018) Immunity 49 6 1132--1147.e7
Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance.
Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15{\%}-30{\%} of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C zeta (PKCzeta) and PKClambda/iota was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKClambda/iota deficiency led to immunogenic cell death and the infiltration of CD8+ T cells, which repressed tumor initiation, PKCzeta loss impaired interferon and CD8+ T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-beta receptor inhibitor plus anti-PD-L1 checkpoint blockade showed synergistic curative activity. Analysis of human samples supported the relevance of these kinases in the immunosurveillance defects of human serrated CRC. These findings provide insight into avenues for the detection and treatment of this poor-prognosis subtype of CRC. View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceJ. H. Choi et al. ( 2019) Science (New York, N.Y.) 364 6440
LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling.
Precise control of Wnt signaling is necessary for immune system development. In this study, we detected severely impaired development of all lymphoid lineages in mice, resulting from an N-ethyl-N-nitrosourea-induced mutation in the limb region 1-like gene (Lmbr1l), which encodes a membrane-spanning protein with no previously described function in immunity. The interaction of LMBR1L with glycoprotein 78 (GP78) and ubiquitin-associated domain-containing protein 2 (UBAC2) attenuated Wnt signaling in lymphocytes by preventing the maturation of FZD6 and LRP6 through ubiquitination within the endoplasmic reticulum and by stabilizing destruction complex" proteins. LMBR1L-deficient T cells exhibited hallmarks of Wnt/beta-catenin activation and underwent apoptotic cell death in response to proliferative stimuli. LMBR1L has an essential function during lymphopoiesis and lymphoid activation acting as a negative regulator of the Wnt/beta-catenin pathway." View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit 17961 EasySep™ Human Naïve Pan T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 17961 Product Name: EasySep™ Human Naïve Pan T Cell Isolation Kit - ReferenceK.-L. Chu et al. (NOV 2018) Mucosal immunology
GITRL on inflammatory antigen presenting cells in the lung parenchyma provides signal 4 for T-cell accumulation and tissue-resident memory T-cell formation.
T-cell responses in the lung are critical for protection against respiratory pathogens. TNFR superfamily members play important roles in providing survival signals to T cells during respiratory infections. However, whether these signals take place mainly during priming in the secondary lymphoid organs and/or in the peripheral tissues remains unknown. Here we show that under conditions of competition, GITR provides a T-cell intrinsic advantage to both CD4 and CD8 effector T cells in the lung tissue, as well as for the formation of CD4 and CD8 tissue-resident memory T cells during respiratory influenza infection in mice. In contrast, under non-competitive conditions, GITR has a preferential effect on CD8 over CD4 T cells. The nucleoprotein-specific CD8 T-cell response partially compensated for GITR deficiency by expansion of higher affinity T cells; whereas, the polymerase-specific response was less flexible and more GITR dependent. Following influenza infection, GITR is expressed on lung T cells and GITRL is preferentially expressed on lung monocyte-derived inflammatory antigen presenting cells. Accordingly, we show that GITR+/+ T cells in the lung parenchyma express more phosphorylated-ribosomal protein S6 than their GITR-/- counterparts. Thus, GITR signaling within the lung tissue critically regulates effector and tissue-resident memory T-cell accumulation. View PublicationCatalog #: Product Name: 19852 EasySep™ Mouse CD4+ T Cell Isolation Kit 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19852 Product Name: EasySep™ Mouse CD4+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceC. L. Araujo Furlan et al. ( 2018) Frontiers in immunology 9 2555
Limited Foxp3+ Regulatory T Cells Response During Acute Trypanosoma cruzi Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8+ T Cell Immunity.
While it is now acknowledged that CD4+ T cells expressing CD25 and Foxp3 (Treg cells) regulate immune responses and, consequently, influence the pathogenesis of infectious diseases, the regulatory response mediated by Treg cells upon infection by Trypanosoma cruzi was still poorly characterized. In order to understand the role of Treg cells during infection by this protozoan parasite, we determined in time and space the magnitude of the regulatory response and the phenotypic, functional and transcriptional features of the Treg cell population in infected mice. Contrary to the accumulation of Treg cells reported in most chronic infections in mice and humans, experimental T. cruzi infection was characterized by sustained numbers but decreased relative frequency of Treg cells. The reduction in Treg cell frequency resulted from a massive accumulation of effector immune cells, and inversely correlated with the magnitude of the effector immune response as well as with emergence of acute immunopathology. In order to understand the causes underlying the marked reduction in Treg cell frequency, we evaluated the dynamics of the Treg cell population and found a low proliferation rate and limited accrual of peripheral Treg cells during infection. We also observed that Treg cells became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. To assess the biological relevance of the relative reduction in Treg cells frequency observed during T. cruzi infection, we transferred in vitro differentiated Treg cells at early moments, when the deregulation of the ratio between regulatory and conventional T cells becomes significant. Intravenous injection of Treg cells dampened parasite-specific CD8+ T cell immunity and affected parasite control in blood and tissues. Altogether, our results show that limited Treg cell response during the acute phase of T. cruzi infection enables the emergence of protective anti-parasite CD8+ T cell immunity and critically influences host resistance. View PublicationCatalog #: Product Name: 19852 EasySep™ Mouse CD4+ T Cell Isolation Kit 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19852 Product Name: EasySep™ Mouse CD4+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceS. R. Walsh et al. (NOV 2018) The Journal of clinical investigation
Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity.
Despite showing success in treating melanoma and haematological malignancies, adoptive cell therapy (ACT) has generated only limited effects in solid tumors. This is, in part, due to a lack of specific antigen targets, poor trafficking/infiltration and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVV) to drive expansion and tumor infiltration of transferred antigen-specific T cells, and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequence when the antigen targeted was a self-protein. However, modulation of IFN$\alpha$/$\beta$ signaling, either by functional blockade or rational choice of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN$\alpha$/$\beta$ in facilitating autoimmune toxicity during cancer immunotherapy and offers a safe and powerful combinatorial regimen with immediate translational applications. View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceA. Wroblewska et al. (NOV 2018) Cell 175 4 1141--1155.e16
Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens.
CRISPR pools are being widely employed to identify gene functions. However, current technology, which utilizes DNA as barcodes, permits limited phenotyping and bulk-cell resolution. To enable novel screening capabilities, we developed a barcoding system operating at the protein level. We synthesized modules encoding triplet combinations of linear epitopes to generate {\textgreater}100 unique protein barcodes (Pro-Codes). Pro-Code-expressing vectors were introduced into cells and analyzed by CyTOF mass cytometry. Using just 14 antibodies, we detected 364 Pro-Code populations; establishing the largest set of protein-based reporters. By pairing each Pro-Code with a different CRISPR, we simultaneously analyzed multiple phenotypic markers, including phospho-signaling, on dozens of knockouts. Pro-Code/CRISPR screens found two interferon-stimulated genes, the immunoproteasome component Psmb8 and a chaperone Rtp4, are important for antigen-dependent immune editing of cancer cells and identified Socs1 as a negative regulator of Pd-l1. The Pro-Code technology enables simultaneous high-dimensional protein-level phenotyping of 100s of genes with single-cell resolution. View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceChen Z et al. (SEP 2017) Cell reports 20 11 2584--2597
miR-150 Regulates Memory CD8 T Cell Differentiation via c-Myb.
MicroRNAs play an important role in T cell responses. However, how microRNAs regulate CD8 T cell memory remains poorly defined. Here, we found that miR-150 negatively regulates CD8 T cell memory in vivo. Genetic deletion of miR-150 disrupted the balance between memory precursor and terminal effector CD8 T cells following acute viral infection. Moreover, miR-150-deficient memory CD8 T cells were more protective upon rechallenge. A key circuit whereby miR-150 repressed memory CD8 T cell development through the transcription factor c-Myb was identified. Without miR-150, c-Myb was upregulated and anti-apoptotic targets of c-Myb, such as Bcl-2 and Bcl-xL, were also increased, suggesting a miR-150-c-Myb survival circuit during memory CD8 T cell development. Indeed, overexpression of non-repressible c-Myb rescued the memory CD8 T cell defects caused by overexpression of miR-150. Overall, these results identify a key role for miR-150 in memory CD8 T cells through a c-Myb-controlled enhanced survival circuit. View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit - ReferenceXu MM et al. (AUG 2017) Immunity 47 2 363--373.e5
Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross-priming through Signal Regulatory Protein α Signaling.
Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPα with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity. Thus, our findings have demonstrated how tumor cells inhibit innate sensing in DCs and suggested that the CD47-SIRPα axis is critical for DC-driven antitumor immunity. View PublicationCatalog #: Product Name: 19853 EasySep™ Mouse CD8+ T Cell Isolation Kit 70025 Human Peripheral Blood Mononuclear Cells, Frozen 18780 EasySep™ Mouse CD11c Positive Selection Kit II Catalog #: 19853 Product Name: EasySep™ Mouse CD8+ T Cell Isolation Kit Catalog #: 70025 Product Name: Human Peripheral Blood Mononuclear Cells, Frozen Catalog #: 18780 Product Name: EasySep™ Mouse CD11c Positive Selection Kit II
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