DOCSLIB.ORG

A CD22–Shp1 Phosphatase Axis Controls Integrin Β7 Display and B

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A CD22–Shp1 Phosphatase Axis Controls Integrin Β7 Display and B ARTICLES https://doi.org/10.1038/s41590-021-00862-z A CD22–Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity Romain Ballet 1,2 ✉ , Martin Brennan1,2,11, Carolin Brandl3,11, Ningguo Feng1,4,5, Jeremy Berri1,2, Julian Cheng1,2, Borja Ocón1,2, Amin Alborzian Deh Sheikh 6, Alex Marki7, Yuhan Bi1,2, Clare L. Abram8, Clifford A. Lowell8, Takeshi Tsubata 6, Harry B. Greenberg1,4,5, Matthew S. Macauley 9,10, Klaus Ley 7, Lars Nitschke3 and Eugene C. Butcher 1,2 ✉ The integrin α4β7 selectively regulates lymphocyte trafficking and adhesion in the gut and gut-associated lymphoid tissue (GALT). Here, we describe unexpected involvement of the tyrosine phosphatase Shp1 and the B cell lectin CD22 (Siglec-2) in the regulation of α4β7 surface expression and gut immunity. Shp1 selectively inhibited β7 endocytosis, enhancing surface α4β7 display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid–dependent manner with integrin β7 on the cell surface to target intracellular Shp1 to β7. Shp1 restrained plasma membrane β7 phosphorylation and inhibited β7 endocytosis without affecting β1 integrin. B cells with reduced Shp1 activity, lacking CD22 or expressing CD22 with mutated Shp1-binding or carbohydrate-binding domains displayed parallel reductions in surface α4β7 and in homing to GALT. Consistent with the spe- cialized role of α4β7 in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses. he integrin α4β7 functions as a B and T cell adhesion recep- inhibitory motif (ITIM) sequences in membrane receptors, often tor for the mucosal vascular addressin (mucosal addressin cell acting in conjunction with ITIM-bearing molecules to inhibit sig- Tadhesion molecule 1 (MAdCAM-1)) expressed by postcapil- naling pathways, including those involved in integrin activity. In lary high endothelial venules (HEVs) in gut-associated lymphoid T cells, for example, Shp1 controls deactivation of the lymphocyte tissue (GALT), by lamina propria venule sites of effector cell recruit- function-associated antigen 1 integrin (αLβ2) to prevent aberrant 1–3 ment and by stromal cells in GALT . GALT is the major site of B adhesion of leukocytes to β2 integrin ligands or T cell adhesion cell activation and humoral immune induction for intestinal immu- to antigen-presenting cells11. In B cells, upon antigen stimulation, nity. Activated B cells undergo isotype class switching in Peyer’s the phosphorylated ITIM sequences of sialic acid-binding Ig-like patches (PPs) and differentiate into migratory immunoglobulin lectin 2 (CD22; also known as Siglec-2) recruit Shp1 to inhibit 2+ A (IgA)-secreting plasmablasts that use α4β7 to home to mucosal downstream components of B cell antigen receptor-induced Ca surfaces4 where local production of secretory IgA provides immune signaling12. However, Shp1 has not been implicated in the control of protection. Presumably in support of this role, B cells home pref- integrin endocytosis or cell-surface expression. erentially to and predominate in murine PPs, contrasting with Here, we report that the pair Shp1/CD22 acts in a cell-intrinsic 5 peripheral lymph nodes (PLNs) where T cells are the majority . This manner to enhance α4β7 surface abundance, with profound organo- homing preference correlates with higher surface expression of α4β7 typic effects on mucosal immune responses. The findings uncover 6 on B cells than on T cells , but the mechanisms responsible for this a selective role for Shp1 in α4β7 endocytosis and surface expression, differential α4β7 surface expression and its essential role in intestinal define CD22 ITIM- and lectin/carbohydrate-dependent mecha- immunity have not been defined. nisms targeting Shp1 to β7 integrin in B cells, and support the The tyrosine phosphatase Src homology region 2 domain- significance of these mechanisms to efficient intestinal antibody containing phosphatase 1 (Shp1; encoded by the gene Ptpn6) has responses. essential roles in regulating immune homeostasis. Homozygous gene depletion of Ptpn6, as described in motheathen mice (Ptpn6me/me), Results 7 results in severe systemic inflammation and death within weeks . Shp1 augments α4β7 cell-surface display in lymphocytes. In stud- Closely related motheathen viable mutant mice (Ptpn6meV/meV) ies of motheaten viable mutant mice (Ptpn6meV/meV) lacking Shp1 express wild-type (WT) levels of Shp1 but the catalytic activity of activity, immunofluorescence staining with antibodies to the α4β7 the enzyme is greatly reduced, resulting in a similar yet slightly less heterodimer or to the β7 subunit revealed a substantial (~90%) severe phenotype8. Shp1 plays essential roles in the regulation of reduction in the median fluorescence intensity (MFI) of Ptpn6meV/ 9,10 meV tyrosine phosphorylation in T and B cells . Shp1 can be targeted splenic naive B cells compared with wild-type controls. The α4 by its binding to phosphorylated immunoreceptor tyrosine-based subunit, which forms heterodimers with integrin β1 as well as β7, 1Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. 2Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. 3Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany. 4Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA. 5Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. 6Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. 7La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA. 8Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA. 9Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada. 10Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada. 11These authors contributed equally: Martin Brennan, Carolin Brandl. ✉e-mail: [email protected]; [email protected] NatURE IMMUnology | VOL 22 | March 2021 | 381–390 | www.nature.com/natureimmunology 381 ARTICLES NATURE IMMUNOLOGY a 750 600 * * WT Isotype control 450 ** 300 * * Ptpn6 meV/meV WT 150 meV/meV 150 ** Ptpn6 *** 0 103 104 105 0 104 105 0 103 104 105 * **** **** ** *** 100 αL β2 β1 50 MFI (percentage of WT) 0 0 103 104 105 0 103 104 105 0 103 104 105 L 2 1 4 7 7 L 2 1 4 7 7 L 2 1 4 7 7 α β β α β β α β β α β β α β β α β β α4 β7 α4β7 α 4 α 4 α 4 Naive B cells CD4+ T cells CD8+ T cells b 200 WT +/meV ** Ptpn6 150 Isotype control ******** **** *** *** **** ******** **** WT Ptpn6 +/meV 100 0 103 104 105 0 104 105 0 103 104 105 αL β2 β1 50 MFI (percentage of WT) 0 0 103 104 105 0 103 104 105 0 103 104 105 α L β 2 β 1 α 4 β 7 β 7 α L β 2 β 1 α 4 β 7 β 7 α L β 2 β 1 α 4 β 7 β 7 4 4 4 α α α α4 β7 α4β7 Naive B cells CD4+ T cells CD8+ T cells meV/meV Fig. 1 | Selective reduction of integrin α4β7 on motheathen viable B and T cells. a,b, Left, flow cytometry of WT versus motheathen viable (Ptpn6 ) (a) +/meV + + or Ptpn6 (b) splenic naive B cells, CD4 T cells and CD8 T cells stained for αL, β2, β1, α4, β7 or α4β7. Shown are pooled data (means ± s.e.m.) from n = 4 experiments with 4–6 (a) or 6–9 (b) animals per group in total. For each animal within one experiment, the MFI of the integrin staining is expressed as a percentage of the mean MFI of the WT group. Right, representative histogram overlays gated in naive B cells. All groups were compared by two-tailed Student’s t-test. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001. was reduced ~20% in Ptpn6meV/meV B cells, reflecting the reduction CD22 deficiency. To address this, we used transgenic animals Y2,5,6F in α4β7. In contrast, we found no reduction for integrins αL, β1 and (CD22 ) in which the CD22 ITIM signaling domains were + + 16 β2 (Fig. 1a). β7 was also reduced on CD4 and CD8 T cells (Fig. 1a). mutated to prevent Shp1 binding and downstream CD22 signaling Since the Ptpn6meV/meV phenotype induces profound changes in the (Fig. 2a). B cells in CD22Y2,5,6F animals express normal amounts of 13 14,15 16 Y2,5,6F phenotype and homeostasis of mature B cells and T cells , we CD22 (ref. ). CD22 B cells displayed surface abundances of α4, –/– repeated the above experiments with heterozygous motheaten via- β7 and α4β7 as severely reduced as on Cd22 B cells, again with no +/meV ble mice (Ptpn6 ). α4, β7 and α4β7 integrins were also reduced on effect on the αL or β1 integrin surface expression (Fig. 2b). +/meV heterozygous Ptpn6 B and T cells, while αL, β1 and β2 were not CD22 is a lectin that interacts in cis with α2-6-sialic acid affected (Fig. 1b). Thus, Shp1 positively regulates the cell-surface (α2-6-Sia)-decorated glycoproteins such as CD22 (ref. 17) or CD45 18 19 abundance of integrin α4β7 on lymphocytes without affecting other (ref. ), affecting its distribution and motility on the B cell surface . integrins. To assess a potential role for the CD22 lectin–carbohydrate interac- tions in cell-autonomous α4β7 regulation, we assessed the integrin CD22 mediates Shp1-dependent α4β7 effects in B cells. The cell-surface levels of B cells expressing a mutated lectin domain selective effect of the Ptpn6+/meV phenotype on B cells suggested (CD22R130E) that prevents α2-6-Sia binding16 (Fig. 2a). CD22R130E B potential involvement of CD22, a B cell-specific lectin known cells expressed CD22 at wild-type levels16 and displayed a significant to recruit Shp1 to the plasma membrane through interactions reduction in α4β7 levels (Fig.
Load more

Recommended publications
  • Binding and Uptake of H-Ferritin Are Mediated by Human Transferrin Receptor-1
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Caltech Authors Binding and uptake of H-ferritin are mediated by human transferrin receptor-1 Li Lia, Celia J. Fanga,b, James C. Ryana,b, Eréne C. Niemib, José A. Lebrónc,1, Pamela J. Björkmanc,d,2, Hisashi Arasee, Frank M. Tortif, Suzy V. Tortig, Mary C. Nakamuraa,b, and William E. Seamana,b,h,2 aDepartment of Medicine, Veterans Administration Medical Center, San Francisco, CA 94121; bDepartment of Medicine, University of California, San Francisco, CA 94143; cDivision of Biology, California Institute of Technology, Pasadena, CA 91125; dHoward Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125; eDepartment of Immunochemistry, World Premier International Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; fDepartment of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157; gDepartment of Biochemistry, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and hDepartment of Microbiology and Immunology, University of California, San Francisco, CA 94143 Contributed by Pamela J. Björkman, November 18, 2009 (sent for review October 5, 2009) − Ferritin is a spherical molecule composed of 24 subunits of two constant of ∼6.5 × 10 7 L/mol and ∼10,000 receptors sites per cell; types, ferritin H chain (FHC) and ferritin L chain (FLC). Ferritin stores subsequently, they endocytose HFt (13). Activated fresh lympho- iron within cells, but it also circulates and binds specifically and cytes also bind HFt (16), as do erythroid precursors, in which the saturably to a variety of cell types.
    [Show full text]
  • Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
    Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only.
    [Show full text]
  • High Efficiency Blood-Brain Barrier Transport Using a VNAR Targeting the Transferrin Receptor 1 (Tfr1)
    bioRxiv preprint doi: https://doi.org/10.1101/816900; this version posted October 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Title: High efficiency blood-brain barrier transport using a VNAR targeting the Transferrin Receptor 1 (TfR1) Authors: Pawel Stocki§, Jaroslaw M Szary§, Charlotte LM Jacobsen¶, Mykhaylo Demydchuk§, Leandra Northall§, Torben Moos¶, Frank S Walsh§ and J Lynn Rutkowski§* §Ossianix, Inc, Stevenage Bioscience Catalyst, Gunnels Wood Rd, Stevenage, Herts, SG1 2FX, UK and 3675 Market St, Philadelphia, PA 19104, USA ¶Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 3, 9220 Aalborg, Denmark Address correspondence to: *J. Lynn Rutkowski, PhD Ossianix, Inc, 3675 Market St., Philadelphia, PA 19104, USA Email: [email protected] Tel: +1(610)291-1724 A one-sentence summary: Development of highly efficient, TfR1 specific, cross-species reactive blood-brain barrier (BBB) shuttle based on shark single domain VNAR antibody. Definitions of all symbols, abbreviations, and acronyms: Transferrin Receptor 1 (TfR1), blood-brain barrier (BBB), Transferrin (Tf), central nervous system (CNS), Variable domain of New Antigen Receptors (VNAR), complementarity-determining region 3 (CDR3), room temperature (RT), size exclusion chromatography (SEC), human serum albumin (HSA), Neurotensin (NT), Immunohistochemistry (IHC), next generation sequencing (NGS), Pharmacokinetic (PK), blood-CSF barrier (BCSFB), Percentage injected dose (%ID), Area under the curve (AUC), attenuated effector function (AEF), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS- PAGE), Western blot (WB), intravenous (IV) 1 bioRxiv preprint doi: https://doi.org/10.1101/816900; this version posted October 30, 2019.
    [Show full text]
  • A CD22-Shp1 Phosphatase Axis Controls Integrin Β7 Display and B Cell Function in Mucosal Immunity
    UCSF UC San Francisco Previously Published Works Title A CD22-Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity. Permalink https://escholarship.org/uc/item/27j4g9rr Journal Nature immunology, 22(3) ISSN 1529-2908 Authors Ballet, Romain Brennan, Martin Brandl, Carolin et al. Publication Date 2021-03-01 DOI 10.1038/s41590-021-00862-z Peer reviewed eScholarship.org Powered by the California Digital Library University of California Europe PMC Funders Group Author Manuscript Nat Immunol. Author manuscript; available in PMC 2021 August 15. Published in final edited form as: Nat Immunol. 2021 March 01; 22(3): 381–390. doi:10.1038/s41590-021-00862-z. Europe PMC Funders Author Manuscripts A CD22-Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity Romain Ballet1,2,#, Martin Brennan1,2,10, Carolin Brandl3,10, Ningguo Feng1,4, Jeremy Berri1,2, Julian Cheng1,2, Borja Ocón1,2, Amin Alborzian Deh Sheikh5, Alex Marki6, Yuhan Bi1,2, Clare L. Abram7, Clifford A. Lowell7, Takeshi Tsubata5, Harry B. Greenberg1,4, Matthew S. Macauley8,9, Klaus Ley6, Lars Nitschke3, Eugene C. Butcher1,2,# 1The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, CA, United States 2Laboratory of Immunology and Vascular Biology, Department of Pathology, School of Medicine, Stanford University, Stanford, CA, United States 3Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen,
    [Show full text]
  • CD22 Antigen Is Broadly Expressed on Lung Cancer Cells and Is a Target for Antibody-Based Therapy
    Published OnlineFirst September 17, 2012; DOI: 10.1158/0008-5472.CAN-12-0173 Cancer Therapeutics, Targets, and Chemical Biology Research CD22 Antigen Is Broadly Expressed on Lung Cancer Cells and Is a Target for Antibody-Based Therapy Joseph M. Tuscano1,2, Jason Kato1, David Pearson3, Chengyi Xiong1, Laura Newell4, Yunpeng Ma1, David R. Gandara1, and Robert T. O'Donnell1,2 Abstract Most patients with lung cancer still die from their disease, necessitating additional options to improve treatment. Here, we provide evidence for targeting CD22, a cell adhesion protein known to influence B-cell survival that we found is also widely expressed in lung cancer cells. In characterizing the antitumor activity of an established anti-CD22 monoclonal antibody (mAb), HB22.7, we showed CD22 expression by multiple approaches in various lung cancer subtypes, including 7 of 8 cell lines and a panel of primary patient specimens. HB22.7 displayed in vitro and in vivo cytotoxicity against CD22-positive human lung cancer cells and tumor xenografts. In a model of metastatic lung cancer, HB22.7 inhibited the development of pulmonary metastasisandextendedoverallsurvival.Thefinding that CD22 is expressed on lung cancer cells is significant in revealing a heretofore unknown mechanism of tumorigenesis and metastasis. Our work suggests that anti- CD22 mAbs may be useful for targeted therapy of lung cancer, a malignancy that has few tumor-specific targets. Cancer Res; 72(21); 5556–65. Ó2012 AACR. Introduction lymphoma (NHL), HB22.7, effectively binds lung cancer cells fi in vitro in vivo In the United States, lung cancer is the most common and mediates speci c and killing.
    [Show full text]
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [Show full text]
  • Mitochondrial Iron Metabolism and Its Role in Neurodegeneration
    Journal of Alzheimer’s Disease 20 (2010) S551–S568 S551 DOI 10.3233/JAD-2010-100354 IOS Press Review Mitochondrial Iron Metabolism and Its Role in Neurodegeneration Maxx P. Horowitza,b,c and J. Timothy Greenamyreb,c,d,∗ aMedical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA bCenter for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA cDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, USA dPittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA Accepted 16 April 2010 Abstract. In addition to their well-established role in providing the cell with ATP, mitochondria are the source of iron-sulfur clusters (ISCs) and heme – prosthetic groups that are utilized by proteins throughout the cell in various critical processes. The post-transcriptional system that mammalian cells use to regulate intracellular iron homeostasis depends, in part, upon the synthesis of ISCs in mitochondria. Thus, proper mitochondrial function is crucial to cellular iron homeostasis. Many neurodegenerative diseases are marked by mitochondrial impairment, brain iron accumulation, and oxidative stress – pathologies that are inter- related. This review discusses the physiological role that mitochondria play in cellular iron homeostasis and, in so doing, attempts to clarify how mitochondrial dysfunction may initiate and/or contribute to iron dysregulation in the context of neurodegenerative disease. We review what is currently known about the entry of iron into mitochondria, the ways in which iron is utilized therein, and how mitochondria are integrated into the system of iron homeostasis in mammalian cells. Lastly, we turn to recent advances in our understanding of iron dysregulation in two neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease), and discuss the use of iron chelation as a potential therapeutic approach to neurodegenerative disease.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Genomic Alterations During the in Situ to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System a C Anne Trinh1,2,3, Carlos R
    Published OnlineFirst December 18, 2020; DOI: 10.1158/1541-7786.MCR-20-0949 MOLECULAR CANCER RESEARCH | CANCER "-OMICS" Genomic Alterations during the In Situ to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System A C Anne Trinh1,2,3, Carlos R. Gil Del Alcazar1,2,3, Sachet A. Shukla1,2,3,4, Koei Chin5,6, Young Hwan Chang5,6, Guillaume Thibault5, Jennifer Eng5, Bojana Jovanovic1,2,3,4, C. Marcelo Aldaz7, So Yeon Park8, Joon Jeong9, Catherine Wu1,2,3,4, Joe Gray5,6, and Kornelia Polyak1,2,3,4 ABSTRACT ◥ The drivers of ductal carcinoma in situ (DCIS) to invasive number aberrations in MHC-I presentation machinery and ductal carcinoma (IDC) transition are poorly understood. Here, losses in 3p, 4q, and 5p are associated with differences in immune we conducted an integrated genomic, transcriptomic, and whole- signaling in estrogen receptor (ER)-negative IDC. Common slideimageanalysistoevaluatechangesincopy-numberprofiles, oncogenic hotspot mutations in genes including TP53 and mutational profiles, expression, neoantigen load, and topology in PIK3CA are predicted to be neoantigens yet are paradoxically 6 cases of matched pure DCIS and recurrent IDC. We demon- conserved during the DCIS-to-IDC transition, and are associated strate through combined copy-number and mutational analysis with differences in immune signaling. We highlight both tumor that recurrent IDC can be genetically related to its pure DCIS and immune-specific changes in the transition of pure DCIS to despite long latency periods and therapeutic interventions. IDC, including genetic changes in tumor cells that may have a Immune “hot” and “cold” tumors can arise as early as DCIS role in modulating immune function and assist in immune and are subtype-specific.
    [Show full text]
  • Gene List HTG Edgeseq Immuno-Oncology Assay
    Gene List HTG EdgeSeq Immuno-Oncology Assay Adhesion ADGRE5 CLEC4A CLEC7A IBSP ICAM4 ITGA5 ITGB1 L1CAM MBL2 SELE ALCAM CLEC4C DST ICAM1 ITGA1 ITGA6 ITGB2 LGALS1 MUC1 SVIL CDH1 CLEC5A EPCAM ICAM2 ITGA2 ITGAL ITGB3 LGALS3 NCAM1 THBS1 CDH5 CLEC6A FN1 ICAM3 ITGA4 ITGAM ITGB4 LGALS9 PVR THY1 Apoptosis APAF1 BCL2 BID CARD11 CASP10 CASP8 FADD NOD1 SSX1 TP53 TRAF3 BCL10 BCL2L1 BIRC5 CASP1 CASP3 DDX58 NLRP3 NOD2 TIMP1 TRAF2 TRAF6 B-Cell Function BLNK BTLA CD22 CD79A FAS FCER2 IKBKG PAX5 SLAMF1 SLAMF7 SPN BTK CD19 CD24 EBF4 FASLG IKBKB MS4A1 RAG1 SLAMF6 SPI1 Cell Cycle ABL1 ATF1 ATM BATF CCND1 CDK1 CDKN1B NCL RELA SSX1 TBX21 TP53 ABL2 ATF2 AXL BAX CCND3 CDKN1A EGR1 REL RELB TBK1 TIMP1 TTK Cell Signaling ADORA2A DUSP4 HES1 IGF2R LYN MAPK1 MUC1 NOTCH1 RIPK2 SMAD3 STAT5B AKT3 DUSP6 HES5 IKZF1 MAF MAPK11 MYC PIK3CD RNF4 SOCS1 STAT6 BCL6 ELK1 HEY1 IKZF2 MAP2K1 MAPK14 NFATC1 PIK3CG RORC SOCS3 SYK CEBPB EP300 HEY2 IKZF3 MAP2K2 MAPK3 NFATC3 POU2F2 RUNX1 SPINK5 TAL1 CIITA ETS1 HEYL JAK1 MAP2K4 MAPK8 NFATC4 PRKCD RUNX3 STAT1 TCF7 CREB1 FLT3 HMGB1 JAK2 MAP2K7 MAPKAPK2 NFKB1 PRKCE S100B STAT2 TYK2 CREB5 FOS HRAS JAK3 MAP3K1 MEF2C NFKB2 PTEN SEMA4D STAT3 CREBBP GATA3 IGF1R KIT MAP3K5 MTDH NFKBIA PYCARD SMAD2 STAT4 Chemokine CCL1 CCL16 CCL20 CCL25 CCL4 CCR2 CCR7 CX3CL1 CXCL12 CXCL3 CXCR1 CXCR6 CCL11 CCL17 CCL21 CCL26 CCL5 CCR3 CCR9 CX3CR1 CXCL13 CXCL5 CXCR2 MST1R CCL13 CCL18 CCL22 CCL27 CCL7 CCR4 CCRL2 CXCL1 CXCL14 CXCL6 CXCR3 PPBP CCL14 CCL19 CCL23 CCL28 CCL8 CCR5 CKLF CXCL10 CXCL16 CXCL8 CXCR4 XCL2 CCL15 CCL2 CCL24 CCL3 CCR1 CCR6 CMKLR1 CXCL11 CXCL2 CXCL9 CXCR5
    [Show full text]
  • A Novel Recombinant Anti-CD22 Immunokinase Delivers
    Published OnlineFirst January 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0685 Large Molecule Therapeutics Molecular Cancer Therapeutics A Novel Recombinant Anti-CD22 Immunokinase Delivers Proapoptotic Activity of Death- Associated Protein Kinase (DAPK) and Mediates Cytotoxicity in Neoplastic B Cells Nils Lilienthal1,2, Gregor Lohmann1, Giuliano Crispatzu1, Elena Vasyutina1, Stefan Zittrich3, Petra Mayer1, Carmen Diana Herling4, Mehmet Kemal Tur5, Michael Hallek4, Gabriele Pfitzer3, Stefan Barth6,7, and Marco Herling1,4 Abstract The serine/threonine death-associated protein kinases (DAPK) SGIII against the B-cell–exclusive endocytic glyco-receptor CD22 provide pro-death signals in response to (oncogenic) cellular stres- was created. Its high purity and large-scale recombinant production ses. Lost DAPK expression due to (epi)genetic silencing is found in a provided a stable, selectively binding, and efficiently internalizing broad spectrum of cancers. Within B-cell lymphomas, deficiency of construct with preserved robust catalytic activity. DK1KD-SGIII the prototypic family member DAPK1 represents a predisposing or specifically and efficiently killed CD22-positive cells of lymphoma early tumorigenic lesion and high-frequency promoter methylation lines and primary CLL samples, sparing healthy donor– or CLL marks more aggressive diseases. On the basis of protein studies and patient–derived non-B cells. The mode of cell death was predom- meta-analyzed gene expression profiling data, we show here that inantly PARP-mediated and caspase-dependent conventional apo- within the low-level context of B-lymphocytic DAPK, particularly ptosis as well as triggering of an autophagic program. The notori- CLL cells have lost DAPK1 expression. To target this potential ously high apoptotic threshold of CLL could be overcome by vulnerability, we conceptualized B-cell–specific cytotoxic reconsti- DK1KD-SGIII in vitro also in cases with poor prognostic features, tution of the DAPK1 tumor suppressor in the format of an immu- such as therapy resistance.
    [Show full text]
  • A Novel Therapeutic Target in Ovarian Cancer Debargha Basuli University of Connecticut - Storrs, [email protected]
    University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 6-8-2016 Iron Addiction In Tumor Initiating Cells: A Novel Therapeutic Target In Ovarian Cancer Debargha Basuli University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Basuli, Debargha, "Iron Addiction In Tumor Initiating Cells: A Novel Therapeutic Target In Ovarian Cancer" (2016). Doctoral Dissertations. 1248. https://opencommons.uconn.edu/dissertations/1248 Iron Addiction In Tumor Initiating Cells: A Novel Therapeutic` Target In Ovarian Cancer Debargha Basuli, M.D., PhD University of Connecticut, 2016 Ovarian cancer is a highly lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), an iron efflux pump, is decreased and transferrin receptor (TFRC), an iron importer, is increased in ovarian cancer tissue. Expression of FPN and TFRC are strongly associated with patient survival. Ovarian cancer tumor-initiating cells demonstrate a similar profile of iron excess. Iron deprivation induced by desferroxamine, knockout of IRP2, or overexpression of FPN preferentially blocks growth of tumor initiating cells. Iron restriction inhibits invasion, synthesis of MMPs and IL6, and reduces intraperitoneal spread of tumor cells in vivo. Growth of ovarian tumors is inhibited by induction of ferroptosis, an iron-dependent form of cell death. Thus, enhanced levels of iron create a metabolic vulnerability that can be exploited therapeutically. We show that this dependence is already evident in the tumor initiating cell and creates a new therapeutic opportunity. Thus, alterations in iron import and export in ovarian cancer result in an iron acquisitive phenotype and an increase in metabolically available iron.
    [Show full text]