Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity.
The immunostimulatory outcome of the interactions of many pathogens with dendritic cells (DCs) has been well characterized. There are many fewer examples of similar interactions between DCs and self-molecules, especially the abnormal self-proteins such as many tumor Ags, and their effects on DC function and the immune response. We show that human epithelial cell Ag MUC1 mucin is recognized in its aberrantly glycosylated form on tumor cells by immature human myeloid DCs as both a chemoattractant (through its polypeptide core) and a maturation and activation signal (through its carbohydrate moieties). On encounter with MUC1, similar to the encounter with LPS, immature DCs increase cell surface expression of CD80, CD86, CD40, and CD83 molecules and the production of IL-6 and TNF-alpha cytokines but fail to make IL-12. When these DCs are cocultured with allogeneic CD4+ T cells, they induce production of IL-13 and IL-5 and lower levels of IL-2, thus failing to induce a type 1 response. Our data suggest that, in vivo in cancer patients, MUC1 attracts immature DCs to the tumor through chemotaxis and subverts their function by negatively affecting their ability to stimulate type 1 helper T cell responses important for tumor rejection.
Carlos
Casey A
CA
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Dong
Hui Fang
HF
Howard
O M Zack
OM
Oppenheim
Joost J
JJ
Hanisch
Franz-Georg
FG
Finn
Olivera J
OJ
D000595:Amino Acid Sequence; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D011487:Protein Conformation; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology; D012794:Sialic Acids / Q000737:chemistry / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
D014408:Biomarkers, Tumor; D018396:Mucin-1; D010446:Peptide Fragments; D020033:Protein Isoforms; D012794:Sialic Acids