title: Gangliosides drive the tumor infiltration and function of myeloid-derived suppressor cells.
abstract: Although it is now widely appreciated that antitumor immunity is critical to impede tumor growth and progression, there remain significant gaps in knowledge about the mechanisms used by tumors to escape immune control. In tumor cells, we hypothesized that one mechanism of immune escape used by tumors involves the synthesis and extracellular shedding of gangliosides, a class of biologically active cell surface glycosphingolipids with known immunosuppressive properties. In this study, we report that tumor cells engineered to be ganglioside deficient exhibit impaired tumorigenicity, supporting a link between ganglioside-dependent immune escape and tumor outgrowth. Notably, we documented a dramatic reduction in the numbers and function of tumor-infiltrating myeloid-derived suppressor cells (MDSC) in ganglioside-deficient tumors, in contrast with the large MDSC infiltrates seen in ganglioside-rich littermate control tumors. Transient ganglioside reconstitution of the tumor cell inoculum was sufficient to increase MDSC infiltration, supporting a direct connection between ganglioside production by tumor cells and the recruitment of immunosuppressive MDSC into the tumor microenvironment. Our results reveal a novel mechanism of immune escape that supports tumor growth, with broad implications given that many human tumors produce and shed high levels of gangliosides.
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, George Washington University School of Medicine, Washington, DC.
authors.forename: Assefa
authors.initials: A
authors.lastname: Wondimu
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, George Washington University School of Medicine, Washington, DC. Departments of Pediatrics, George Washington University School of Medicine, Washington, DC.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, George Washington University School of Medicine, Washington, DC.
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, George Washington University School of Medicine, Washington, DC.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bobb
authors.affiliation: Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, George Washington University School of Medicine, Washington, DC.
authors.forename: Jennifer S Y
authors.initials: JS
authors.lastname: Ma
authors.affiliation: Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, George Washington University School of Medicine, Washington, DC.
authors.forename: Lina
authors.initials: L
authors.lastname: Chakrabarti
authors.affiliation: Departments of Pediatrics, George Washington University School of Medicine, Washington, DC. Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, George Washington University School of Medicine, Washington, DC.
authors.forename: Saša
authors.initials: S
authors.lastname: Radoja
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, George Washington University School of Medicine, Washington, DC. Departments of Pediatrics, George Washington University School of Medicine, Washington, DC. Department of Biochemistry/Molecular Biology, George Washington University School of Medicine, Washington, DC. sladisch@cnmc.org.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ladisch
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D005434:Flow Cytometry; D005732:Gangliosides / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000473:pathology*
chemical_list: D005732:Gangliosides