Degradation of the tumor antigen epitope gp100(280-288) by fibroblast-associated enzymes abolishes specific immunorecognition.
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.
Albo
Federica
F
Dipartimento di Neuroscienze, Università degli Studi di Roma Tor Vergata, Rome, Italy.
Cavazza
Antonella
A
Giardina
Bruno
B
Marini
Mario
M
Roda
L Giorgio
LG
Schumacher
Reto
R
Spagnoli
Giulio C
GC
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000626:Aminopeptidases / Q000378:metabolism*; D002268:Carboxypeptidases / Q000378:metabolism*; D002478:Cells, Cultured; D000939:Epitopes / Q000276:immunology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D010446:Peptide Fragments; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D058951:gp100 Melanoma Antigen
D000596:Amino Acids; D000939:Epitopes; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D010455:Peptides; D058951:gp100 Melanoma Antigen; C548641:gp100(280-288) melanoma antigen peptide; D002268:Carboxypeptidases; D000626:Aminopeptidases