Degradation of the tumor antigen epitope gp100(280-288) by fibroblast-associated enzymes abolishes specific immunorecognition.

Abstract

Degradation of the tumor antigen epitope gp100(280-288) (YLEPGPVTA) was investigated in the presence of cultured human fibroblasts, and acellular supernatants obtained from these cells; the possible effect of substrate degradation on in vitro immunorecognition was also addressed. In the presence of fibroblasts, gp100(280-288) was degraded to free amino acids with a half-life of less than 4 min; hydrolysis data support the hypothesis that substrate degradation was mainly caused by the activity of cell-expressed amino- and carboxypeptidases. Gp100(280-288) was also degraded in the presence of acellular supernatants: under these conditions, the hydrolysis pattern was similar to that observed in the presence of whole cells, but degradation kinetics was slower. As a result of these phenomena, immunorecognition of gp100(280-288)-specific cytotoxic T lymphocyte (CTL) clones was severely hampered, and was totally suppressed after 90 min. In conclusion, the high activity of fibroblast-expressed proteases, and the presence of wide-scope soluble enzymes, may explain, at least in part, the low activity of peptide-based antineoplastic vaccines, as well as the transient effectiveness of subcutaneously administered peptides in general.

• Authors: Federica Albo, Antonella Cavazza, Bruno Giardina, Mario Marini, L Giorgio Roda, Reto Schumacher, Giulio C Spagnoli
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1671 Issue 1-3 Pg. 59-69 (Mar 17 2004) ISSN: 0006-3002 [Print] Netherlands
• PMID: 15026146 (Publication Type: Journal Article)

Chemical References

• Amino Acids
• Epitopes
• Membrane Glycoproteins
• Neoplasm Proteins
• PMEL protein, human
• Peptide Fragments
• Peptides
• gp100 Melanoma Antigen
• gp100(280-288) melanoma antigen peptide
• Carboxypeptidases
• Aminopeptidases

Topics

• Amino Acid Sequence
• Amino Acids (metabolism)
• Aminopeptidases (metabolism)
• Carboxypeptidases (metabolism)
• Cells, Cultured
• Epitopes (immunology, metabolism)
• Fibroblasts (cytology, enzymology)
• Humans
• Membrane Glycoproteins (genetics, immunology, metabolism)
• Neoplasm Proteins (genetics, immunology, metabolism)
• Peptide Fragments
• Peptides (genetics, immunology, metabolism)
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• gp100 Melanoma Antigen