title: Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice.
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.
authors: Oncology Research Institute, Loyola University Medical Center, Loyola University Chicago, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.
authors: Jonathan M
authors: JM
authors: Eby
authors: Oncology Research Institute, Loyola University Medical Center, Loyola University Chicago, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.|Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors: Levi
authors: L
authors: Barse
authors: Oncology Research Institute, Loyola University Medical Center, Loyola University Chicago, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.
authors: Steven W
authors: SW
authors: Henning
authors: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Martijn J W E
authors: MJ
authors: Rabelink
authors: Oncology Research Institute, Loyola University Medical Center, Loyola University Chicago, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.|Department of Immunology and Microbiology, University of Colorado Denver, Denver, CO, USA.
authors: Jared
authors: J
authors: Klarquist
authors: Department of Medicine, Loyola University Chicago, Maywood, IL, USA.
authors: Emily R
authors: ER
authors: Gilbert
authors: Oncology Research Institute, Loyola University Medical Center, Loyola University Chicago, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.|Burn and Shock Trauma Institute, Loyola University Chicago, Maywood, IL, USA.
authors: Adam M
authors: AM
authors: Hammer
authors: Oncology Research Institute, Loyola University Medical Center, Loyola University Chicago, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.
authors: Manuel F
authors: MF
authors: Fernandez
authors: Oncology Research Institute, Loyola University Medical Center, Loyola University Chicago, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.
authors: Nathan
authors: N
authors: Yung
authors: Oakton Community College, Des Plaines, IL, USA.
authors: Safia
authors: S
authors: Khan
authors: Illinois Mathematics and Science Academy, Aurora, IL, USA.
authors: Hannah G
authors: HG
authors: Miller
authors: Department of Medicine, Loyola University Chicago, Maywood, IL, USA.
authors: Edward R
authors: ER
authors: Kessler
authors: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors: Elizabeth
authors: E
authors: Garrett-Mayer
authors: Department of Medicine, Loyola University Chicago, Maywood, IL, USA.
authors: Daniel F
authors: DF
authors: Dilling
authors: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Rob C
authors: RC
authors: Hoeben
authors: Oncology Research Institute, Loyola University Medical Center, Loyola University Chicago, Rm 203, 2160 S. 1st Avenue, Maywood, IL, 60153, USA. ilepool@luc.edu.|Departments of Pathology, Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA. ilepool@luc.edu.
authors: I Caroline
authors: IC
authors: Le Poole
mesh_terms: D000818:Animals; D019470:Biolistics; D045744:Cell Line, Tumor; D005732:Gangliosides / Q000096:biosynthesis* / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000276:immunology* / Q000628:therapy; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012799:Sialyltransferases / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D005732:Gangliosides; D019444:Vaccines, DNA; C026226:ganglioside, GD3; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; C106770:ST8SIA5 protein, human
keywords: Adenovirus; Ganglioside D3; Neuroendocrine tumors; Sialyltransferase; Vaccine