Pancreas carcinoma antigen fused to invariant chain elicits T-cell response and tumor growth inhibition.
OBJECTIVE
The major histocompatibility complex class II chaperone invariant chain (Ii) is widely used as a carrier for inserted antigenic sequences and their introduction into the class II processing pathway. The tumor-associated antigen core 2beta 1,6 N-acetylglucosaminyltransferase (C2GnT), a glycosyltransferase present in human pancreatic tumor cells, is not expressed by normal pancreatic tissues.


METHODS
A set of expression vectors was engineered where the class II binding region of Ii was replaced by C2GnT-derived sequences. We investigated in vitro whether dendritic cells transfected with Ii-C2GnT constructs were capable to stimulate proliferation of CD4 T cells. We also tested whether vaccination with Ii-C2GnT would protect mice from tumor development.


RESULTS
Invariant chain-C2GnT fusion proteins bind to human DR1, DR3, DR4 and to mouse I-A molecules. Our results demonstrate that the plasmid DNA encoding the C2GnT epitope embedded in Ii induces tumor-specific T-cell responses. Mice immunized with the Ii constructs showed reduced growth of Panc02 pancreatic tumor cells.


CONCLUSIONS
Therefore, Ii clipped with the tumor-associated antigen C2GnT shows promise for the treatment of pancreatic cancer.
Nagaraj
Srinivas
S
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Neumann
Juergen
J
Winzen
Bettina
B
Frank
Susanne
S
Ziske
Carsten
C
Sievers
Elisabeth
E
Koch
Norbert
N
Schmidt-Wolf
Ingo G H
IG
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019556:COS Cells; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013997:Time Factors; D014162:Transfection
D000944:Antigens, Differentiation, B-Lymphocyte; D019496:Cancer Vaccines; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D011993:Recombinant Fusion Proteins; C045084:invariant chain; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase