Abstract
Tumors exploit several strategies to evade immune recognition, including the production of a large number of immunosuppressive factors, which leads to reduced numbers and impaired functions of dendritic cells (DCs) in the vicinity of tumors. We have investigated whether a mucin released by tumor cells could be involved in causing these immunomodulating effects on DCs. We used a recombinant purified form of the MUC1 glycoprotein, an epithelial associated mucin that is overexpressed, aberrantly glycosylated, and shed during cancer transformation. The O-glycosylation profile of the recombinant MUC1 glycoprotein (ST-MUC1) resembled that expressed by epithelial tumors in vivo, consisting of large numbers of sialylated core 1 (sialyl-T, ST) oligosaccharides. When cultured in the presence of ST-MUC1, human monocyte-derived DCs displayed a modified phenotype with decreased expression of costimulatory molecules (CD86, CD40), Ag-presenting molecules (DR and CD1d), and differentiation markers (CD83). In contrast, markers associated with an immature phenotype, CD1a and CD206 (mannose receptor), were increased. This effect was already evident at day 4 of DC culture and was dose dependent. The modified phenotype of DCs corresponded to an altered balance in IL-12/IL-10 cytokine production, with DC expressing an IL-10highIL-12low phenotype after exposure to ST-MUC1. These DCs were defective in their ability to induce immune responses in both allogeneic and autologous settings, as detected in proliferation and ELISPOT assays. The altered DC differentiation and Ag presentation function induced by the soluble sialylated tumor-associated mucin may represent a mechanism by which epithelial tumors can escape immunosurveillance.
| Original language | English |
|---|---|
| Pages (from-to) | 7764-7772 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 174 |
| Issue number | 12 |
| Publication status | Published - Jun 15 2005 |
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ASJC Scopus subject areas
- Immunology
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Recombinant tumor-associated MUC1 glycoprotein impairs the differentiation and function of dendritic cells. / Rughetti, Aurelia; Pellicciotta, Ilenia; Biffoni, Mauro; Bäckström, Malin; Link, Thomas; Bennet, Eric P.; Clausen, Henrik; Noll, Thomas; Hansson, Gunnar C.; Burchell, Joy M.; Frati, Luigi; Taylor-Papadimitriou, Joyce; Nuti, Marianna.
In: Journal of Immunology, Vol. 174, No. 12, 15.06.2005, p. 7764-7772.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Recombinant tumor-associated MUC1 glycoprotein impairs the differentiation and function of dendritic cells
AU - Rughetti, Aurelia
AU - Pellicciotta, Ilenia
AU - Biffoni, Mauro
AU - Bäckström, Malin
AU - Link, Thomas
AU - Bennet, Eric P.
AU - Clausen, Henrik
AU - Noll, Thomas
AU - Hansson, Gunnar C.
AU - Burchell, Joy M.
AU - Frati, Luigi
AU - Taylor-Papadimitriou, Joyce
AU - Nuti, Marianna
PY - 2005/6/15
Y1 - 2005/6/15
N2 - Tumors exploit several strategies to evade immune recognition, including the production of a large number of immunosuppressive factors, which leads to reduced numbers and impaired functions of dendritic cells (DCs) in the vicinity of tumors. We have investigated whether a mucin released by tumor cells could be involved in causing these immunomodulating effects on DCs. We used a recombinant purified form of the MUC1 glycoprotein, an epithelial associated mucin that is overexpressed, aberrantly glycosylated, and shed during cancer transformation. The O-glycosylation profile of the recombinant MUC1 glycoprotein (ST-MUC1) resembled that expressed by epithelial tumors in vivo, consisting of large numbers of sialylated core 1 (sialyl-T, ST) oligosaccharides. When cultured in the presence of ST-MUC1, human monocyte-derived DCs displayed a modified phenotype with decreased expression of costimulatory molecules (CD86, CD40), Ag-presenting molecules (DR and CD1d), and differentiation markers (CD83). In contrast, markers associated with an immature phenotype, CD1a and CD206 (mannose receptor), were increased. This effect was already evident at day 4 of DC culture and was dose dependent. The modified phenotype of DCs corresponded to an altered balance in IL-12/IL-10 cytokine production, with DC expressing an IL-10highIL-12low phenotype after exposure to ST-MUC1. These DCs were defective in their ability to induce immune responses in both allogeneic and autologous settings, as detected in proliferation and ELISPOT assays. The altered DC differentiation and Ag presentation function induced by the soluble sialylated tumor-associated mucin may represent a mechanism by which epithelial tumors can escape immunosurveillance.
AB - Tumors exploit several strategies to evade immune recognition, including the production of a large number of immunosuppressive factors, which leads to reduced numbers and impaired functions of dendritic cells (DCs) in the vicinity of tumors. We have investigated whether a mucin released by tumor cells could be involved in causing these immunomodulating effects on DCs. We used a recombinant purified form of the MUC1 glycoprotein, an epithelial associated mucin that is overexpressed, aberrantly glycosylated, and shed during cancer transformation. The O-glycosylation profile of the recombinant MUC1 glycoprotein (ST-MUC1) resembled that expressed by epithelial tumors in vivo, consisting of large numbers of sialylated core 1 (sialyl-T, ST) oligosaccharides. When cultured in the presence of ST-MUC1, human monocyte-derived DCs displayed a modified phenotype with decreased expression of costimulatory molecules (CD86, CD40), Ag-presenting molecules (DR and CD1d), and differentiation markers (CD83). In contrast, markers associated with an immature phenotype, CD1a and CD206 (mannose receptor), were increased. This effect was already evident at day 4 of DC culture and was dose dependent. The modified phenotype of DCs corresponded to an altered balance in IL-12/IL-10 cytokine production, with DC expressing an IL-10highIL-12low phenotype after exposure to ST-MUC1. These DCs were defective in their ability to induce immune responses in both allogeneic and autologous settings, as detected in proliferation and ELISPOT assays. The altered DC differentiation and Ag presentation function induced by the soluble sialylated tumor-associated mucin may represent a mechanism by which epithelial tumors can escape immunosurveillance.
UR - http://www.scopus.com/inward/record.url?scp=20444403424&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20444403424&partnerID=8YFLogxK
M3 - Article
C2 - 15944279
AN - SCOPUS:20444403424
VL - 174
SP - 7764
EP - 7772
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 12
ER -