Pancreas carcinoma antigen fused to invariant chain elicits T-cell response and tumor growth inhibition.

Abstract

OBJECTIVES:

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.

• Authors: Srinivas Nagaraj, Juergen Neumann, Bettina Winzen, Susanne Frank, Carsten Ziske, Elisabeth Sievers, Norbert Koch, Ingo G H Schmidt-Wolf
• Journal: Pancreas (Pancreas) Vol. 37 Issue 3 Pg. 321-7 (Oct 2008) ISSN: 1536-4828 [Electronic] United States
• PMID: 18815556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation, B-Lymphocyte
• Cancer Vaccines
• HLA-DR Antigens
• Histocompatibility Antigens Class II
• Recombinant Fusion Proteins
• invariant chain
• N-Acetylglucosaminyltransferases
• beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase

Topics

• Animals
• Antigens, Differentiation, B-Lymphocyte (genetics, immunology)
• CD4-Positive T-Lymphocytes (immunology)
• COS Cells
• Cancer Vaccines (genetics, immunology)
• Cell Line, Tumor
• Cell Proliferation
• Chlorocebus aethiops
• Dendritic Cells (immunology)
• HLA-DR Antigens (immunology)
• Histocompatibility Antigens Class II (genetics, immunology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• N-Acetylglucosaminyltransferases (genetics, immunology)
• Pancreatic Neoplasms (immunology, pathology, therapy)
• Recombinant Fusion Proteins (immunology)
• Time Factors
• Transfection