Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy

Abstract

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.

Tenascin-C: Exploitation and collateral damage in cancer management

“…Using a proteomic approach, a human leukocyte antigen (HLA) class I allele A*02-associated GBM peptidome was identified based on 32 GBM stage IV tissue samples. 60 This analysis resulted to a set of 309 tumor-associated peptides (TUMAPs) that could be assigned to 148 different genes. Further in-depth analysis and validation studies let to a selection of 10 peptides that are highly expressed in GBM and at the same time showed the ability to elicit strong antigen-specific T cell responses in vitro.…”

“…Using patientderived T cell clones that are specific for 2 of the 10 peptides showed cytotoxic activity against GBM cells in vitro. 60 The vaccine IMA950 comprises 9 TUMAPs eliciting cytotoxic T lymphocytes and 2 TUMAPs that target T-helper cells. Using IMA950, 3 phase 1 clinical studies have been initiated (Table 1) and final results have been presented recently at the ESMO 2014 congress for the trial conducted by Cancer Research UK.…”

Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors

“…8 Cellular immunotherapies have been explored 9 and could allow the elimination of deep brain infiltrative tumor cells. GBM-specific tumor antigens (Ag) recognized by ab T cells, 10 stress-induced molecules activating gd T cells or specific surface molecules that can trigger ADCC have been identified and proposed for effective immunotherapies in GBM. 11 Clinical trials have been performed by systemic or intracranial infusion of ex vivo-amplified T lymphocytes from either the GBM tumor, draining lymph nodes, or HLA-mismatched T cells from healthy donors, 12 but have had limited success.…”

Analysis of Major Histocompatibility Complex (MHC) Immunopeptidomes Using Mass Spectrometry*

“…1, upper panel). In general, ϳ1 g of tissue is required to detect hundreds to thousands of MHC class I peptides (41). In fact, the amount of starting material needed for the detection of high numbers of peptides is inversely proportional to the expression levels of MHC molecules.…”