A mutant chaperone converts a wild-type protein into a tumor-specific antigen.
Monoclonal antibodies have become important therapeutic agents against certain cancers. Many tumor-specific antigens are mutant proteins that are predominantly intracellular and thus not readily accessible to monoclonal antibodies. We found that a wild-type transmembrane protein could be transformed into a tumor-specific antigen. A somatic mutation in the chaperone gene Cosmc abolished function of a glycosyltransferase, disrupting O-glycan Core 1 synthesis and creating a tumor-specific glycopeptidic neo-epitope consisting of a monosaccharide and a specific wild-type protein sequence. This epitope induced a high-affinity, highly specific, syngeneic monoclonal antibody with antitumor activity. Such tumor-specific glycopeptidic neo-epitopes represent potential targets for monoclonal antibody therapy.
Schietinger
Andrea
A
Department of Pathology, Committee on Immunology, Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA. aschieti@uchicago.edu
Philip
Mary
M
Yoshida
Barbara A
BA
Azadi
Parastoo
P
Liu
Hui
H
Meredith
Stephen C
SC
Schreiber
Hans
H
D000116:Acetylgalactosamine / Q000032:analysis; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000915:Antibody Affinity; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000032:analysis; D001483:Base Sequence; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D005700:Galactosyltransferases / Q000378:metabolism; D006031:Glycosylation; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D000098853:Podoplanin
D000116:Acetylgalactosamine; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D000939:Epitopes; D005700:Galactosyltransferases; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C514310:Cosmc protein, mouse; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C040286:Tn antigen