The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells.
Immunity to tumor Ags in patients is typically weak and not therapeutic. We have identified a new mechanism by which potentially immunogenic glycoprotein tumor Ags, such as MUC1, fail to stimulate strong immune responses. MUC1 is a heavily glycosylated membrane protein that is also present in soluble form in sera and ascites of cancer patients. We show that this soluble protein is readily taken up by dendritic cells (DC), but is not transported to late endosomes or MHC class II compartments for processing and binding to class II MHC. MUC1 uptake is mediated by the mannose receptor, and the protein is then retained long term in early endosomes without degradation. Long-term retention of MUC1 does not interfere with the ability of DC to process and present other Ags. We also demonstrate inhibited processing of another important glycoprotein tumor Ag, HER-2/neu. This may, therefore, be a frequent obstacle to presentation of tumor Ags and an important consideration in the design of cancer vaccines. It should be possible to overcome this obstacle by providing DC with a form of tumor Ag that can be better processed. For MUC1 we show that a 140-aa-long synthetic peptide is very efficiently processed by DC.
Hiltbold
E M
EM
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261, USA.
Vlad
A M
AM
Ciborowski
P
P
Watkins
S C
SC
Finn
O J
OJ
D000595:Amino Acid Sequence; D019138:Antibodies, Blocking / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D001692:Biological Transport / Q000187:drug effects / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000648:ultrastructure; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D006433:Hemocyanins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007424:Intracellular Fluid / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type; D008351:Mannans / Q000494:pharmacology; D008358:Mannose / Q000494:pharmacology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000097:blood / Q000276:immunology* / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D013997:Time Factors
D019138:Antibodies, Blocking; D006433:Hemocyanins; D037181:Lectins, C-Type; D008351:Mannans; D008358:Mannose; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D018396:Mucin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; C032808:keyhole-limpet hemocyanin