19 results on '"Mangani D"'
Search Results
2. Co-inhibition of the TGF-β and VEGF pathways in glioblastoma
- Author
-
Mangani, D, University of Zurich, and Mangani, D
- Subjects
UZHDISS UZH Dissertations ,610 Medicine & health ,10040 Clinic for Neurology - Published
- 2017
3. P08.36 TGF-β pathway-mediated escape from VEGF blockade is linked with angiogenesis and immune-suppression in murine glioma models
- Author
-
Mangani, D., primary, Weller, M., additional, Seyed Sadr, E., additional, Willscher, E., additional, Seystahl, K., additional, Reifenberger, G., additional, Tabatabai, G., additional, Binder, H., additional, and Schneider, H., additional
- Published
- 2017
- Full Text
- View/download PDF
4. Dietary protein modulates intestinal dendritic cells to establish mucosal homeostasis.
- Author
-
Moreira TG, Cox LM, Da Silva P, Mangani D, De Oliveira MG, Escobar G, Lanser TB, Murphy L, Lobo ELC, Milstein O, Gauthier CD, Clara Guimarāes A, Schwerdtfeger L, Ekwudo MN, Wasén C, Liu S, Menezes GB, Ferreira E, Gabriely G, Anderson AC, Faria AMC, Rezende RM, and Weiner HL
- Subjects
- Animals, Mice, Immune Tolerance, T-Lymphocytes, Regulatory immunology, Mice, Inbred C57BL, Gene Expression Regulation, Immunity, Mucosal, Dendritic Cells immunology, Dendritic Cells metabolism, Dietary Proteins, Homeostasis, Gastrointestinal Microbiome immunology, Intestinal Mucosa immunology, Intestinal Mucosa metabolism
- Abstract
Dietary proteins are taken up by intestinal dendritic cells (DCs), cleaved into peptides, loaded to major histocompatibility complexes, and presented to T cells to generate an immune response. Amino acid (AA)-diets do not have the same effects because AAs cannot bind to major histocompatibility complex to activate T cells. Here, we show that impairment in regulatory T cell generation and loss of tolerance in mice fed a diet lacking whole protein is associated with major transcriptional changes in intestinal DCs including downregulation of genes related to DC maturation, activation and decreased gene expression of immune checkpoint molecules. Moreover, the AA-diet had a profound effect on microbiome composition, including an increase in Akkermansia muciniphilia and Oscillibacter and a decrease in Lactococcus lactis and Bifidobacterium. Although microbiome transfer experiments showed that AA-driven microbiome modulates intestinal DC gene expression, most of the unique transcriptional change in DC was linked to the absence of whole protein in the diet. Our findings highlight the importance of dietary proteins for intestinal DC function and mucosal tolerance., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
5. A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.
- Author
-
Mertens RT, Misra A, Xiao P, Baek S, Rone JM, Mangani D, Sivanathan KN, Arojojoye AS, Awuah SG, Lee I, Shi GP, Petrova B, Brook JR, Anderson AC, Flavell RA, Kanarek N, Hemberg M, and Nowarski R
- Subjects
- Animals, Mice, Humans, Mice, Inbred C57BL, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Mice, Knockout, Fatty Acids metabolism, Intestines immunology, Immunity, Innate, Inflammation immunology, Inflammation metabolism, Glycolysis, Oxidation-Reduction, Interleukin-18 metabolism, Interleukin-18 immunology, Nucleotides, Cyclic metabolism, Macrophages immunology, Macrophages metabolism, Immune Tolerance
- Abstract
Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
6. Pan-cancer mapping of single CD8 + T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity.
- Author
-
Tooley K, Jerby L, Escobar G, Krovi SH, Mangani D, Dandekar G, Cheng H, Madi A, Goldschmidt E, Lambden C, Krishnan RK, Rozenblatt-Rosen O, Regev A, and Anderson AC
- Subjects
- Animals, Humans, Mice, Mice, Inbred C57BL, Neoplasms immunology, Neoplasms genetics, Neoplasms pathology, Signal Transduction, Single-Cell Analysis methods, Tumor Microenvironment immunology, CD28 Antigens metabolism, CD28 Antigens genetics, CD28 Antigens immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Hepatocyte Nuclear Factor 1-alpha metabolism, Hepatocyte Nuclear Factor 1-alpha genetics, Receptors, CXCR6 metabolism, Receptors, CXCR6 genetics
- Abstract
CD8
+ T cells must persist and function in diverse tumor microenvironments to exert their effects. Thus, understanding common underlying expression programs could better inform the next generation of immunotherapies. We apply a generalizable matrix factorization algorithm that recovers both shared and context-specific expression programs from diverse datasets to a single-cell RNA sequencing (scRNA-seq) compendium of 33,161 CD8+ T cells from 132 patients with seven human cancers. Our meta-single-cell analyses uncover a pan-cancer T cell dysfunction program that predicts clinical non-response to checkpoint blockade in melanoma and highlights CXCR6 as a pan-cancer marker of chronically activated T cells. Cxcr6 is trans-activated by AP-1 and repressed by TCF1. Using mouse models, we show that Cxcr6 deletion in CD8+ T cells increases apoptosis of PD1+ TIM3+ cells, dampens CD28 signaling, and compromises tumor growth control. Our study uncovers a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8+ cell responses and is essential for effective anti-tumor immunity., Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, ExcepGen, and Zumutor Biologics, which have interests in cancer immunotherapy. A.C.A. is also a paid consultant for iTeos Therapeutics and Larkspur Biosciences. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict-of-interest policies. O.R.-R. is an employee of Genentech. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov. From August 1, 2020, A.R. is an employee of Genentech and has equity in Roche. When at the Broad, A.R.’s interests were reviewed and managed by the Broad Institute, MIT and HHMI in accordance with their conflict-of-interest policies. A provisional patent application was filed including work in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
7. Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling.
- Author
-
Cadinu P, Sivanathan KN, Misra A, Xu RJ, Mangani D, Yang E, Rone JM, Tooley K, Kye YC, Bod L, Geistlinger L, Lee T, Mertens RT, Ono N, Wang G, Sanmarco L, Quintana FJ, Anderson AC, Kuchroo VK, Moffitt JR, and Nowarski R
- Subjects
- Animals, Humans, Mice, Fibroblasts metabolism, Fibroblasts pathology, In Situ Hybridization, Fluorescence methods, Inflammation metabolism, Inflammation pathology, Cell Communication, Gastrointestinal Tract metabolism, Gastrointestinal Tract pathology, Colitis metabolism, Colitis pathology, Colitis, Ulcerative metabolism, Colitis, Ulcerative pathology
- Abstract
Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues., Competing Interests: Declaration of interests J.R.M. is a co-founder of, stakeholder in, and advisor for Vizgen, Inc. J.R.M. is an inventor on patents associated with MERFISH applied for on his behalf by Harvard University and Boston Children’s Hospital. J.R.M.’s interests were reviewed and are managed by Boston Children’s Hospital in accordance with their conflict-of-interest policies. R.N. is a paid consultant for Quris-AI. V.K.K. has an ownership interest in Tizona Therapeutics, Trishula Therapeutics, Celsius Therapeutics, Bicara Therapeutics, Larkspur Therapeutics. V.K.K. has financial interests in Biocon Biologic, Compass, Elpiscience Biopharmaceutical Ltd, Equilium Inc, PerkinElmer, and Syngene Intl. V.K.K. is a member of SABs for Cell Signaling Technology, Elpiscience Biopharmaceutical Ltd, GlaxoSmithKline, Larkspur, Novartis Sabatolimab, Tizona Therapeutics, Tr1X, and Werewolf. A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Nekonal Sarl. A.C.A. is also a paid consultant for iTeos Therapeutics, Larkspur Biosciences, and Excepgen. R.N., V.K.K., and A.C.A.’s interests were reviewed and managed by Mass General Brigham in accordance with their conflict-of-interest policies., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
8. CD304 + adipose tissue-derived mesenchymal stem cell abundance in autologous fat grafts highly correlates with improvement of localized pain syndromes.
- Author
-
Rezzonico Jost T, Lozito A, Mangani D, Raimondi A, Klinger F, Morone D, Klinger M, Grassi F, and Vinci V
- Subjects
- Humans, Adipose Tissue transplantation, Pain metabolism, Syndrome, Cell Differentiation, Cells, Cultured, Mesenchymal Stem Cells
- Abstract
Abstract: Surgery, burns or surgery-free accident are leading causes of scars with altered tissue consistency, a reduced degree of motion and pain. Autologous fat grafting can dramatically improve tissue consistency and elasticity but less frequently results in the reduction of pain. Therefore, we analyzed different cell populations present within the adipose tissue to be engrafted and correlated them with the reduction of pain after surgery. Here, we identify a population of CD3 - CD4 - CD304 + cells present in grafted adipose tissue, whose abundance highly correlates with pain improvement shortly after surgery ( r2 = 0.7243****) as well as persistently over time (3 months later: r2 = 0.6277****, 1 year later: r2 = 0.5346***, and 4 years later: r2 = 0.5223***). These cells are characterized by the absence of the hematopoietic marker CD45, whereas they express CD90 and CD34, which characterize mesenchymal stem cells (MSCs); the concomitant presence of CD10 and CD73 in the plasma membrane supports a function of these cells in pain reduction. We deduce that the enrichment of this adipose tissue-derived MSC subset could enhance the therapeutic properties of adipose grafts and ameliorate localized pain syndromes., (Copyright © 2023 International Association for the Study of Pain.)
- Published
- 2024
- Full Text
- View/download PDF
9. Tumor immunogenicity dictates reliance on TCF1 in CD8 + T cells for response to immunotherapy.
- Author
-
Escobar G, Tooley K, Oliveras JP, Huang L, Cheng H, Bookstaver ML, Edwards C, Froimchuk E, Xue C, Mangani D, Krishnan RK, Hazel N, Rutigliani C, Jewell CM, Biasco L, and Anderson AC
- Subjects
- Humans, Antibodies, Antigens, Neoplasm, Immunotherapy, CD8-Positive T-Lymphocytes, T Cell Transcription Factor 1 genetics, Neoplasms immunology, Neoplasms therapy
- Abstract
Stem-like CD8
+ T cells are regulated by T cell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1+ CD8+ T cells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8+ T cells and ICB response in poorly immunogenic tumors that accumulate TOX+ dysfunctional T cells, but is dispensable for T cell priming and therapy response in highly immunogenic tumors that efficiently expand transitory effectors. Importantly, improving T cell priming by vaccination or by enhancing antigen presentation on tumors rescues the defective responses of TCF1-deficient CD8+ T cells upon ICB in poorly immunogenic tumors. Our study highlights TCF1's role during the early stages of anti-tumor CD8+ T cell responses with important implications for guiding optimal therapeutic interventions in cancers with low TCF1+ CD8+ T cells and low-neo-antigen expression., Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Excepgen, which have interests in cancer immunotherapy. A.C.A. is a paid consultant for iTeos Therapeutics and Larkspur Biosciences. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital. C.M.J. is an employee of the VA Maryland Health Care System. The views reported here do not reflect the views of the VA or United States Government. C.M.J. has an equity position with Cartesian Therapeutics. L.B. is also an employee of SANA Biotechnology, Inc. Neither SANA Biotechnology nor its subsidiaries have conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
10. Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling.
- Author
-
Cadinu P, Sivanathan KN, Misra A, Xu RJ, Mangani D, Yang E, Rone JM, Tooley K, Kye YC, Bod L, Geistlinger L, Lee T, Ono N, Wang G, Sanmarco L, Quintana FJ, Anderson AC, Kuchroo VK, Moffitt JR, and Nowarski R
- Abstract
Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used MERFISH to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations; charted their spatial organization; and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues., Competing Interests: Declaration of interests J.R.M is a co-founder of, stake-holder in, and advisor for Vizgen, Inc. J.R.M. is an inventor on patents associated with MERFISH applied for on his behalf by Harvard University and Boston Children’s Hospital. J.R.M.’s interests were reviewed and are managed by Boston Children’s Hospital in accordance with their conflict-of-interest policies. A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Nekonal Sarl. A.C.A. is also a paid consultant for iTeos Therapeutics, Larkspur Biosciences, and Excepgen. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Additional authors in this manuscript declare no competing financial interests.
- Published
- 2023
- Full Text
- View/download PDF
11. Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19.
- Author
-
G Moreira T, Gauthier CD, Murphy L, Lanser TB, Paul A, Matos KTF, Mangani D, Izzy S, Rezende RM, Healy BC, Baecher-Allan CM, Chitnis T, Kuchroo V, and Weiner HL
- Subjects
- Animals, Humans, Mice, Administration, Intranasal, GTP-Binding Proteins, Membrane Proteins, rho-Associated Kinases, SARS-CoV-2, T-Lymphocytes, Transforming Growth Factor beta1 genetics, Antibodies, Monoclonal therapeutic use, COVID-19
- Abstract
T cells are present in early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully human anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using serum proteomics and RNA-sequencing, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100 μg/d) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab-treated subjects and NGK7
+ effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1 , and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes, and B cells in subjects treated with Foralumab. In addition to the downregulation of effector features, an increase in TGFB1 gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases signaling was downregulated in Foralumab-treated individuals. TGFB1, GIMAP7 , and NKG7 transcriptomic changes observed in Foralumab-treated COVID-19 subjects were also observed in healthy volunteers, MS subjects, and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.- Published
- 2023
- Full Text
- View/download PDF
12. Learning from the nexus of autoimmunity and cancer.
- Author
-
Mangani D, Yang D, and Anderson AC
- Subjects
- Humans, Autoimmunity, T-Lymphocytes, Immune Tolerance, Self Tolerance, Neoplasms therapy, Autoimmune Diseases therapy
- Abstract
The immune system plays critical roles in both autoimmunity and cancer, diseases at opposite ends of the immune spectrum. Autoimmunity arises from loss of T cell tolerance against self, while in cancer, poor immunity against transformed self fails to control tumor growth. Blockade of pathways that preserve self-tolerance is being leveraged to unleash immunity against many tumors; however, widespread success is hindered by the autoimmune-like toxicities that arise in treated patients. Knowledge gained from the treatment of autoimmunity can be leveraged to treat these toxicities in patients. Further, the understanding of how T cell dysfunction arises in cancer can be leveraged to induce a similar state in autoreactive T cells. Here, we review what is known about the T cell response in autoimmunity and cancer and highlight ways in which we can learn from the nexus of these two diseases to improve the application, efficacy, and management of immunotherapies., Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Nekonal Sarl. A.C.A. is also a paid consultant for iTeos Therapeutics, Larkspur Biosciences, and Excepgen. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict-of-interest policies., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
13. PD-L1 + and XCR1 + dendritic cells are region-specific regulators of gut homeostasis.
- Author
-
Moreira TG, Mangani D, Cox LM, Leibowitz J, Lobo ELC, Oliveira MA, Gauthier CD, Nakagaki BN, Willocq V, Song A, Guo L, Lima DCA, Murugaiyan G, Butovsky O, Gabriely G, Anderson AC, Rezende RM, Faria AMC, and Weiner HL
- Subjects
- Animals, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, Colitis genetics, Colitis immunology, Colitis metabolism, Cytokines immunology, Cytokines metabolism, Dendritic Cells metabolism, Feces microbiology, Female, Gastrointestinal Microbiome genetics, Gastrointestinal Microbiome immunology, Homeostasis genetics, Humans, Intestinal Mucosa metabolism, Intestinal Mucosa microbiology, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptors, Chemokine genetics, Receptors, Chemokine metabolism, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transcriptome genetics, Transcriptome immunology, Mice, B7-H1 Antigen immunology, Dendritic Cells immunology, Homeostasis immunology, Intestinal Mucosa immunology, Receptors, Chemokine immunology
- Abstract
The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1
+ DC in the duodenal LP and XCR1+ DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1+ and XCR1+ DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1+ and XCR1+ DC as region-specific physiologic regulators of intestinal homeostasis., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
14. T cell factor 1: A master regulator of the T cell response in disease.
- Author
-
Escobar G, Mangani D, and Anderson AC
- Subjects
- Animals, Autoimmune Diseases drug therapy, Cell Communication drug effects, Cell Communication immunology, Cell Differentiation genetics, Cell Differentiation immunology, Chromatin Assembly and Disassembly drug effects, Chromatin Assembly and Disassembly immunology, Chronic Disease drug therapy, Disease Models, Animal, Gene Expression Regulation drug effects, Gene Expression Regulation immunology, Humans, Immunologic Factors pharmacology, Immunologic Factors therapeutic use, Immunologic Memory drug effects, Immunologic Memory genetics, Neoplasms drug therapy, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Virus Diseases drug therapy, Wnt Signaling Pathway drug effects, Wnt Signaling Pathway genetics, Wnt Signaling Pathway immunology, Autoimmune Diseases immunology, Neoplasms immunology, T Cell Transcription Factor 1 metabolism, T-Lymphocytes immunology, Virus Diseases immunology
- Abstract
Recent advances have redefined a role for T cell factor 1 (TCF1) that goes beyond T cell development and T memory formation and encompasses new functions in the regulation of T cell biology. Here, we discuss the multifaceted and context-dependent role of TCF1 in peripheral T cells, particularly during disease-induced inflammatory states such as autoimmunity, cancer, and chronic infections. Understanding how TCF1 fine-tunes peripheral T cell biology holds the potential to tailor improved immune-targeted therapies., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
- Full Text
- View/download PDF
15. Endogenous Glucocorticoid Signaling Regulates CD8 + T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment.
- Author
-
Acharya N, Madi A, Zhang H, Klapholz M, Escobar G, Dulberg S, Christian E, Ferreira M, Dixon KO, Fell G, Tooley K, Mangani D, Xia J, Singer M, Bosenberg M, Neuberg D, Rozenblatt-Rosen O, Regev A, Kuchroo VK, and Anderson AC
- Subjects
- Animals, CD8-Positive T-Lymphocytes cytology, Cell Line, Tumor, Hematopoiesis immunology, Hepatocyte Nuclear Factor 1-alpha biosynthesis, Immune Checkpoint Inhibitors, Lymphocyte Activation immunology, Macrophages immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Signal Transduction immunology, CD8-Positive T-Lymphocytes immunology, Glucocorticoids metabolism, Macrophages metabolism, Melanoma, Experimental pathology, Tumor Microenvironment immunology
- Abstract
Identifying signals in the tumor microenvironment (TME) that shape CD8
+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy., Competing Interests: Declaration of Interests A.C.A. is a member of the SAB for Tizona Therapeutics, Compass Therapeutics, Zumutor Biologics, and Astellas Global Pharma Development, which have interests in cancer immunotherapy. V.K.K. is a member of the SAB for Astellas Global Pharma Development and has an ownership interest and is a member of the SAB for Tizona Therapeutics. A.R. and V.K.K. are co-founders of and have an ownership interest in Celsius Therapeutics. A.C.A.’s and V.K.K.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict of interest policies. M.B. is a consultant for Eli Lilly and Company. A.R. is also an SAB member for Thermo Fisher, Neogene Therapeutics, Asimov, and Syros Pharmaceuticals and is an equity holder in Immunitas. A.R.’s interests were reviewed and managed by the Broad Institute and HHMI in accordance with their conflict of interest policies. A provisional patent application was filed including work in this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
16. The network of immunosuppressive pathways in glioblastoma.
- Author
-
Mangani D, Weller M, and Roth P
- Subjects
- Brain Neoplasms therapy, Glioblastoma therapy, Humans, Immune Tolerance, Immunotherapy, Brain Neoplasms immunology, Glioblastoma immunology
- Abstract
Glioblastoma remains a fatal tumor despite increased knowledge regarding the complex signalling pathways that drive this devastating disease. Recently, immunotherapeutic approaches have shown remarkable and durable responses in various cancers including metastatic melanoma and advanced non-small cell lung cancer. So far, it remains unclear whether these immunotherapeutics may also work against glioblastoma and other tumors residing in the central nervous system. It is well known that patients with glioblastoma suffer from profound local immunosuppression that represents the major hurdle to overcome in the context of immunotherapy. Several studies have demonstrated that this immunosuppressive phenotype is orchestrated by glioma-derived membrane-bound and soluble factors as well as the particular microenvironment within the brain. Here, we discuss the molecular and cellular pathways involved in glioblastoma-mediated inhibition of the immune system and highlight possible treatment approaches aiming at reinvigorating anti-tumor immune responses., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
17. Limited role for transforming growth factor-β pathway activation-mediated escape from VEGF inhibition in murine glioma models.
- Author
-
Mangani D, Weller M, Seyed Sadr E, Willscher E, Seystahl K, Reifenberger G, Tabatabai G, Binder H, and Schneider H
- Subjects
- Angiogenesis Inhibitors administration & dosage, Animals, Bevacizumab administration & dosage, Cell Line, Tumor, Cell Survival drug effects, Disease Models, Animal, Lymphotoxin-alpha antagonists & inhibitors, Phosphorylation, Pyrazoles administration & dosage, Quinolines administration & dosage, Signal Transduction, Smad2 Protein metabolism, Brain Neoplasms metabolism, Glioma metabolism, Lymphotoxin-alpha metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
Background: The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-β pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition., Methods: The role of the TGF-β pathway in escape from VEGF inhibition was assessed in vitro and in vivo and by gene expression profiling in syngeneic mouse glioma models., Results: We found that TGF-β is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-β pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-β receptor 1 antagonist LY2157299 in 2 of 4 models. Reduction of tumor volume and blood vessel density, but not induction of hypoxia, correlated with benefit from B20-4.1.1. Reduction of phosphorylated (p)SMAD2 by LY2157299 was seen in all models but did not predict survival. Resistance to B20 was associated with anti-angiogenesis escape pathway gene expression, whereas resistance to LY2157299 was associated with different immune response gene signatures in SMA-497 and GL-261 on transcriptomic profiling. The combination of B20 with LY2157299 was ineffective in SMA-497 but provided prolongation of survival in GL-261, associated with early suppression of pSMAD2 in tumor and host immune cells, prolonged suppression of angiogenesis, and delayed accumulation of tumor infiltrating microglia/macrophages., Conclusions: Our study highlights the biological heterogeneity of murine glioma models and illustrates that cotargeting of the VEGF and TGF-β pathways might lead to improved tumor control only in subsets of glioblastoma., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
- Full Text
- View/download PDF
18. MiR-221/222 target the DNA methyltransferase MGMT in glioma cells.
- Author
-
Quintavalle C, Mangani D, Roscigno G, Romano G, Diaz-Lagares A, Iaboni M, Donnarumma E, Fiore D, De Marinis P, Soini Y, Esteller M, and Condorelli G
- Subjects
- Antineoplastic Agents, Alkylating pharmacology, Apoptosis genetics, Cell Line, Tumor, DNA Damage drug effects, DNA Damage genetics, Dacarbazine analogs & derivatives, Dacarbazine pharmacology, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Glioma metabolism, Humans, Temozolomide, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Glioma genetics, MicroRNAs genetics, RNA Interference, RNA, Messenger genetics, Tumor Suppressor Proteins genetics
- Abstract
Glioblastoma multiforme (GBM) is one of the most deadly types of cancer. To date, the best clinical approach for treatment is based on administration of temozolomide (TMZ) in combination with radiotherapy. Much evidence suggests that the intracellular level of the alkylating enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) impacts response to TMZ in GBM patients. MGMT expression is regulated by the methylation of its promoter. However, evidence indicates that this is not the only regulatory mechanism present. Here, we describe a hitherto unknown microRNA-mediated mechanism of MGMT expression regulation. We show that miR-221 and miR-222 are upregulated in GMB patients and that these paralogues target MGMT mRNA, inducing greater TMZ-mediated cell death. However, miR-221/miR-222 also increase DNA damage and, thus, chromosomal rearrangements. Indeed, miR-221 overexpression in glioma cells led to an increase in markers of DNA damage, an effect rescued by re-expression of MGMT. Thus, chronic miR-221/222-mediated MGMT downregulation may render cells unable to repair genetic damage. This, associated also to miR-221/222 oncogenic potential, may poor GBM prognosis.
- Published
- 2013
- Full Text
- View/download PDF
19. Emerging molecular networks in Burkitt's lymphoma.
- Author
-
Mangani D, Roberti A, Rizzolio F, and Giordano A
- Subjects
- ADP-Ribosylation Factors metabolism, Burkitt Lymphoma metabolism, Burkitt Lymphoma pathology, Cyclin-Dependent Kinase Inhibitor p16 metabolism, DNA Methylation, Genetic Loci, Humans, MicroRNAs genetics, MicroRNAs metabolism, Proteasome Endopeptidase Complex genetics, Proteasome Endopeptidase Complex metabolism, Proteolysis, Proto-Oncogene Proteins c-myc metabolism, Signal Transduction, Ubiquitin genetics, Ubiquitin metabolism, ADP-Ribosylation Factors genetics, Burkitt Lymphoma genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc genetics
- Abstract
Burkitt's lymphoma (BL), one of the most aggressive tumors affecting humans, characterized by the constitutive activation of the Myc oncogene together with the alteration of many other genetic and epigenetic factors. Among them, the INK4a/ARF locus has been well documented to play a central role in BL. Recently, we have discovered that simultaneous deregulation of both DNA methylation patterns and the ubiquitin-dependent proteolysis system is required to completely inactive the INK4/ARF locus, opening new possibilities for treating Burkitt's lymphoma. In this review, we integrate our discovery with the general view of BL and propose a new comprehensive approach to analyze and manage this aggressive disease., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.