RESUMEN
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.
Asunto(s)
Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Péptidos/inmunología , Presentación de Antígeno/fisiología , Antígenos CD/metabolismo , Antígenos de Neoplasias/química , Antígenos de Neoplasias/uso terapéutico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Linfocitos T CD8-positivos/inmunología , Cromatografía Liquida , Citocinas/metabolismo , Citometría de Flujo , Perfilación de la Expresión Génica , Proteína Ácida Fibrilar de la Glía/metabolismo , Glioblastoma/patología , Glioblastoma/terapia , Antígenos HLA-A/análisis , Antígenos HLA-A/química , Antígenos HLA-A/inmunología , Humanos , Espectrometría de Masas , Análisis de Secuencia por Matrices de Oligonucleótidos , Péptidos/análisis , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , ARN Mensajero/metabolismo , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismo , Análisis de Secuencia de ProteínaRESUMEN
The exact pathophysiology of contrast-induced nephropathy (CIN) is not fully clarified, yet the osmotic characteristics of contrast media (CM) have been a significant focus in many investigations of CIN. Osmotic effects of CM specific to the kidney include transient decreases in blood flow, filtration fraction, and glomerular filtration rate. Potentially significant secondary effects include an osmotically induced diuresis with a concomitant dehydrating effect. Clinical experiences that have compared the occurrence of CIN between the various classes of CM based on osmolality have suggested a much less than anticipated advantage, if any, with a lower osmolality. Recent animal experiments actually suggest that induction of a mild osmotic diuresis in association with iso-osmolar agents tends to offset potentially deleterious renal effects of high viscosity-mediated intratubular CM stagnation.