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 glycoprot ein tumor Ags, such as MUC1, fail to stimulate strong immune responses, MUC 1 is a heavily glycosylated membrane protein that is also present in solubl e form in sera and ascites of cancer patients, We show that this soluble pr otein is readily taken up by dendritic cells (DC), but is not transported t o 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 pro tein is then retained long term in early endosomes without degradation, Lon g-term retention of MUC1 does not interfere with the ability of DC to proce ss and present other Ags, We also demonstrate inhibited processing of anoth er important glycoprotein tumor Ag, HER-2/neu. This may, therefore, be a fr equent obstacle to presentation of tumor Ags and an important consideration in the design of cancer vaccines, It should be possible to overcome this o bstacle by providing DC with a form of tumor Ag that can be better processe d, For MUC1 we show that a 140-aa-long synthetic peptide is very efficientl y processed by DC.