A tumor-associated glycoprotein that blocks MHC class II-dependent antigen presentation by dendritic cells.
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.
Gutzmer
Ralf
R
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Li
Wei
W
Sutterwala
Shaheen
S
Lemos
Maria P
MP
Elizalde
J Ignasi
JI
Urtishak
Sandra L
SL
Behrens
Edward M
EM
Rivers
Patricia M
PM
Schlienger
Katia
K
Laufer
Terri M
TM
Eck
Stephen L
SL
Marks
Michael S
MS
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
D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II