title: A tumor-associated glycoprotein that blocks MHC class II-dependent antigen presentation by dendritic cells.
abstract: Tumors evade immune surveillance despite the frequent expression of tumor-associated Ags (TAA). Tumor cells escape recognition by CD8(+) T cells through several mechanisms, including down-regulation of MHC class I molecules and associated Ag-processing machinery. However, although it is well accepted that optimal anti-tumor immune responses require tumor-reactive CD4(+) T cells, few studies have addressed how tumor cells evade CD4(+) T cell recognition. In this study, we show that a common TAA, GA733-2, and its murine orthologue, mouse epithelial glycoprotein (mEGP), function in blocking MHC class II-restricted Ag presentation by dendritic cells. GA733-2 is a common TAA that is expressed normally at low levels by some epithelial tissues and a subset of dendritic cells, but at high levels on colon, breast, lung, and some nonepithelial tumors. We show that ectopic expression of mEGP or GA733-2, respectively, in dendritic cells derived from murine bone marrow or human monocytes results in a dose-dependent inability to stimulate proliferation of Ag-specific or alloreactive CD4(+) T cells. Dendritic cells exposed to cell debris from tumors expressing mEGP are similarly compromised. Furthermore, mice immunized with dendritic cells expressing mEGP from a recombinant adenovirus vector exhibited a muted anti-adenovirus immune response. The inhibitory effect of mEGP was not due to down-regulation of functional MHC class II molecules or active suppression of T cells, and did not extend to T cell responses to superantigen. These results demonstrate a novel mechanism by which tumors may evade CD4(+) T cell-dependent immune responses through expression of a TAA.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gutzmer
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Shaheen
authors.initials: S
authors.lastname: Sutterwala
authors.forename: Maria P
authors.initials: MP
authors.lastname: Lemos
authors.forename: J Ignasi
authors.initials: JI
authors.lastname: Elizalde
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Urtishak
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Rivers
authors.forename: Katia
authors.initials: K
authors.lastname: Schlienger
authors.forename: Terri M
authors.initials: TM
authors.lastname: Laufer
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Eck
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D066298:In Vitro Techniques; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II