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Inhibition of Serine‐Peptidase Activity Enhances the Generation of a Survivin‐Derived HLA‐A2‐Presented CTL Epitope in Colon‐Carcinoma Cells
Author(s) -
Preta G.,
Marescotti D.,
Fortini C.,
Carcoforo P.,
Castelli C.,
Masucci M.,
Gavioli R.
Publication year - 2008
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2008.02175.x
Subject(s) - epitope , ctl* , cytotoxic t cell , biology , survivin , major histocompatibility complex , mhc class i , antigen processing , antigen , cd8 , immune system , antigen presentation , cell culture , cancer research , human leukocyte antigen , microbiology and biotechnology , t cell , immunology , in vitro , biochemistry , genetics
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.