Identification of tumor antigens among the HLA peptidomes of glioblastoma tumors and plasma

Shraibman, Bracha, Barnea, Eilon, Kadosh, Dganit Melamed, Haimovich, Yael, Slobodin, Gleb, Rosner, Itzhak, López-Larrea, Carlos, Hilf, Norbert, Kuttruff, Sabrina, Song, Colette, Britten, Cedrik, Castle, John, Kreiter, Sebastian, Frenzel, Katrin, Tatagiba, Marcos, Tabatabai, Ghazaleh, Dietrich, Pierre Yves, Dutoit, Valérie, Wick, Wolfgang, Platten, Michael, Winkler, Frank, Von Deimling, Andreas, Kroep, Judith, Sahuquillo, Juan, Martinez-Ricarte, Francisco, Rodon, Jordi, Lassen, Ulrik, Ottensmeier, Christian, Van der Burg, Sjoerd H., Straten, Per Thor, Skovgaard Poulsen, Hans, Ponsati, Berta, Okada, Hideho, Rammensee, Hans Georg, Sahin, Ugur, Singh, Harpreet and Admon, Arie (2019) Identification of tumor antigens among the HLA peptidomes of glioblastoma tumors and plasma. Molecular and Cellular Proteomics, 18 (6), 1255-1268. (doi:10.1074/mcp.RA119.001524).

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis to most patients. Immunotherapy of GBM is a potentially beneficial treatment option, whose optimal implementation may depend on familiarity with tumor specific antigens, presented as HLA peptides by the GBM cells. Further, early detection of GBM, such as by a routine blood test, may improve survival, even with the current treatment modalities. This study includes large-scale analyses of the HLA peptidome (immunopeptidome) of the plasma-soluble HLA molecules (sHLA) of 142 plasma samples, and the membranal HLA of GBM tumors of 10 of these patients’ tumor samples. Tumor samples were fresh-frozen immediately after surgery and the plasma samples were collected before, and at multiple visits after surgery. In total, this HLA peptidome analysis involved 52 different HLA allotypes and resulted in the identification of more than 35,000 different HLA peptides. Strong correlations were observed in the signal intensities and in the repertoires of identified peptides between the tumors and plasma-soluble HLA peptidomes of the individual patients, whereas low correlations were observed between these HLA peptidomes and the tumors’ proteomes. HLA peptides derived from Cancer/Testis Antigens (CTAs) were selected based on their presence among the HLA peptidomes of the patients and absence of expression of their source genes from any healthy and essential human tissues, except from immune-privileged sites. Additionally, peptides were selected as potential biomarkers if their levels in the plasma-sHLA peptidome were significantly reduced after the removal of tumor mass. The CTAs identified among the analyzed HLA peptidomes provide new opportunities for personalized immunotherapy and for early diagnosis of GBM.

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