The melanoma inhibitor of apoptosis protein: a target for spontaneous cytotoxic T cell responses.
The identification of tumor antigens which expression is essential for the survival of tumor cells is a new avenue to prevent antigen loss variants emerging due to immunoselection, particularly during immune therapy. The melanoma inhibitor of apoptosis protein, ML-IAP (also named livin) counteracts apoptosis induced by death receptors, hypooxgenic conditions, or chemotherapeutic agents. Thus, elevated expression of ML-IAP renders melanoma cells resistant to apoptotic stimuli and thereby potentially contributes to the oncogenic phenotype. Here, we demonstrate that T cells in a large proportion of melanoma patients infiltrating the tumor or circulating in the peripheral blood specifically recognize ML-IAP-derived peptides. Interestingly, the responses against the peptide epitope ML-IAP280-289 were not restricted to melanoma patients but present among peripheral blood T cells in a few healthy controls. In situ peptide/HLA-A2 multimer staining, however, confirmed the infiltration of ML-IAP-reactive cells into the tumor microenvironment. Moreover, ML-IAP-reactive T cells isolated by magnetic beads coated with peptide/HLA-A2 complexes were cytotoxic against HLA-matched melanoma cells. In conclusion, out data strongly indicate ML-IAP as a suitable target for immunologic intervention.
Andersen
Mads Hald
MH
Tumor Immunology Group, Danish Cancer Society, Copenhagen, Denmark. mha@cancer.dk
Reker
Sine
S
Becker
Jürgen C
JC
thor Straten
Per
P
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D018189:Immunomagnetic Separation; D051034:Inhibitor of Apoptosis Proteins; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D002352:Carrier Proteins; D015789:HLA-A2 Antigen; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments