Identification of Tumor Antigens Among the HLA Peptidomes of Glioblastoma Tumors and Plasma

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. Furthermore, 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.

CIITA-Transduced Glioblastoma Cells Uncover a Rich Repertoire of Clinically Relevant Tumor-Associated HLA-II Antigens

“…While not much is known about TAA-derived HLA-II ligands in GBM, the repertoire of HLA-I ligands has been more intensively explored in recent years (9,59,60) In case of observed multiple specificity or redundancy, motifs are indicated accordingly. NA; not assigned.…”

“…Therefore, we first verified that known GBM-associated TAAs are presented on HLA-I molecules in our three investigated GBM lines. We compared the HLA-I antigenic repertoire to the repertoire reported in a recent study where a large scale HLA-I related antigen discovery was performed in tens of GBM tissues and plasma samples(59). Shraibaman et al shortlisted 134 cancer-testis antigens (CTAs) of high clinical interest that are expressed at a very low level in healthy tissues from…”

Tumor-Specific T Cell Activation in Malignant Brain Tumors

“…An HLA peptidome paper that used 3 glioblastoma cell lines could show the induction of CTAs by the chemotherapeutic drug decitabine, which however is not commonly used to treat glioblastoma (71). A recent analysis of plasma-soluble HLA ligands found a strong correlation between plasma ligands and tumor tissue derived ligands, but a weak correlation between both plasma and tumor tissue derived peptidomes and the tumors proteoms (108).…”

A model of antigen processing improves prediction of MHC I-presented peptides

“…We refer to the other samples, in which exact MHC I restrictions were not experimentally determined, as the MULTIALLELIC samples. We divided these into two groups: MUTLIALLELIC-OLD, comprised of 56 experiments from eight studies published before 2018 [12][13][14][15][16][17][18][19] , and MULTIALLELIC-RECENT, comprised of 20 experiments from two studies published in 2019 10,20 .…”