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Dutoit, Herold-Mende, Hilf, Schoor, Beckhove, Bucher, Dorsch, Flohr, Fritsche, Lewandrowski, Lohr, Rammensee, Stevanovic, Trautwein, Vass, Walter, Walker, Weinschenk, Singh-Jasuja, Dietrich (2012) Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy Brain 135(Pt 4) 1042-54


Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02(+) glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8(+) T cells in vitro. In vivo, glioblastoma-specific CD8(+) T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastoma.


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