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Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice

Authors
  • Eby, Jonathan M.1
  • Barse, Levi1, 2
  • Henning, Steven W.1
  • Rabelink, Martijn J. W. E.3
  • Klarquist, Jared1, 4
  • Gilbert, Emily R.5
  • Hammer, Adam M.1, 6
  • Fernandez, Manuel F.1
  • Yung, Nathan1
  • Khan, Safia7
  • Miller, Hannah G.8
  • Kessler, Edward R.5
  • Garrett-Mayer, Elizabeth9
  • Dilling, Daniel F.5
  • Hoeben, Rob C.3
  • Le Poole, I. Caroline1, 10
  • 1 Loyola University Chicago, Oncology Research Institute, Loyola University Medical Center, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA , Maywood (United States)
  • 2 Northwestern University, Feinberg School of Medicine, Department of Pharmacology, Chicago, IL, USA , Chicago (United States)
  • 3 Leiden University Medical Center, Department of Molecular Cell Biology, Leiden, The Netherlands , Leiden (Netherlands)
  • 4 University of Colorado Denver, Department of Immunology and Microbiology, Denver, CO, USA , Denver (United States)
  • 5 Loyola University Chicago, Department of Medicine, Maywood, IL, USA , Maywood (United States)
  • 6 Loyola University Chicago, Burn and Shock Trauma Institute, Maywood, IL, USA , Maywood (United States)
  • 7 Oakton Community College, Des Plaines, IL, USA , Des Plaines (United States)
  • 8 Illinois Mathematics and Science Academy, Aurora, IL, USA , Aurora (United States)
  • 9 Medical University of South Carolina, Department of Public Health Sciences, Charleston, SC, USA , Charleston (United States)
  • 10 Loyola University Chicago, Departments of Pathology, Microbiology and Immunology, Maywood, IL, USA , Maywood (United States)
Type
Published Article
Journal
Cancer Immunology Immunotherapy
Publisher
Springer-Verlag
Publication Date
Oct 27, 2016
Volume
66
Issue
1
Pages
63–75
Identifiers
DOI: 10.1007/s00262-016-1920-8
Source
Springer Nature
Keywords
License
Yellow

Abstract

An immunotherapeutic strategy is discussed supporting anti-tumor activity toward malignancies overexpressing ganglioside D3. GD3 can be targeted by NKT cells when derived moieties are presented in the context of CD1d. NKT cells can support anti-tumor responses by secreting inflammatory cytokines and through cytotoxicity toward CD1d+GD3+ tumors. To overexpress GD3, we generated expression vector DNA and an adenoviral vector encoding the enzyme responsible for generating GD3 from its ubiquitous precursor GM3. We show that DNA encoding α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (SIAT8) introduced by gene gun vaccination in vivo leads to overexpression of GD3 and delays tumor growth. Delayed tumor growth is dependent on CD1d expression by host immune cells, as shown in experiments engaging CD1d knockout mice. A trend toward greater NKT cell populations among tumor-infiltrating lymphocytes is associated with SIAT8 vaccination. A single adenoviral vaccination introduces anti-tumor activity similarly to repeated vaccination with naked DNA. Here, greater NKT tumor infiltrates were accompanied by marked overexpression of IL-17 in the tumor, later switching to IL-4. Our results suggest that a single intramuscular adenoviral vaccination introduces overexpression of GD3 by antigen-presenting cells at the injection site, recruiting NKT cells that provide an inflammatory anti-tumor environment. We propose adenoviral SIAT8 (AdV-SIAT8) can slow the growth of GD3 expressing tumors in patients.

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