Inhibition of serine-peptidase activity enhances the generation of a survivin-derived HLA-A2-presented CTL epitope in colon-carcinoma cells

G. Preta, D. Marescotti, C. Fortini, P. Carcoforo, C. Castelli, M. Masucci, R. Gavioli

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Cytotoxic T lymphocytes eliminate tumor cells expressing antigenic peptides in the context of MHC-I molecules. Peptides are generated during protein degradation by the proteasome and resulting products, surviving cytosolic amino-peptidases activity, may be presented by MHC-I molecules. The MHC-I processing pathway is altered in a large number of malignancies and modulation of antigen generation is one strategy employed by cells to evade immune control. In this study we analyzed the generation and presentation of a survivin-derived CTL epitope in HLA-A2-positive colon-carcinoma cells. Although all cell lines expressed the anti-apoptotic protein survivin, some tumors were poorly recognized by ELTLGEFLKL (ELT)-specific CTL cultures. The expression of MHC-I or TAP molecules was similar in all cell lines suggesting that tumors not recognized by CTLs may present defects in the generation of the ELT-epitope which could be due either to lack of generation or to subsequent degradation of the epitope. The cells were analyzed for the expression and the activity of extra-proteasomal peptidases. A significant overexpression and higher activity of TPPII was observed in colon-carcinoma cells which are not killed by ELT-specific CTLs, suggesting a possible role of TPPII in the degradation of the ELT-epitope. To confirm the role of TPPII in the degradation of the ELT-peptide, we showed that treatment of colon-carcinoma cells with a TPPII inhibitor resulted in a dose-dependent increased sensitivity to ELT-specific CTLs. These results suggest that TPPII is involved in degradation of the ELT-peptide, and its overexpression may contribute to the immune escape of colon-carcinoma cells.

Original languageEnglish
Pages (from-to)579-588
Number of pages10
JournalScandinavian Journal of Immunology
Volume68
Issue number6
DOIs
Publication statusPublished - Dec 2008

Fingerprint

HLA-A2 Antigen
Serine
Epitopes
Colon
Peptide Hydrolases
Carcinoma
Peptides
Neoplasms
Apoptosis Regulatory Proteins
Cytotoxic T-Lymphocytes
Proteasome Endopeptidase Complex
Tumor Cell Line
Proteolysis
Antigens
Cell Line

ASJC Scopus subject areas

  • Immunology

Cite this

Inhibition of serine-peptidase activity enhances the generation of a survivin-derived HLA-A2-presented CTL epitope in colon-carcinoma cells. / Preta, G.; Marescotti, D.; Fortini, C.; Carcoforo, P.; Castelli, C.; Masucci, M.; Gavioli, R.

In: Scandinavian Journal of Immunology, Vol. 68, No. 6, 12.2008, p. 579-588.

Research output: Contribution to journalArticle

Preta, G. ; Marescotti, D. ; Fortini, C. ; Carcoforo, P. ; Castelli, C. ; Masucci, M. ; Gavioli, R. / Inhibition of serine-peptidase activity enhances the generation of a survivin-derived HLA-A2-presented CTL epitope in colon-carcinoma cells. In: Scandinavian Journal of Immunology. 2008 ; Vol. 68, No. 6. pp. 579-588.
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AU - Masucci, M.

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