Abstract
Glioblastoma multiforme (GBM) presents the most malignant form of glioma, with a 5-year survival rate below 3% despite standard therapy. Novel immune-based therapies in improving treatment outcomes in GBM are therefore warranted. Several molecularly defined targets have been identified mediating anti-GBM cellular immune responses. Mesothelin is a tumor-associated antigen (TAA) which is expressed in several solid tumors with different histology. Here, we report the immunological significance of mesothelin in human malignant glioma. Expression of mature, surface-bound mesothelin protein was found to bein human GBM defined by immunofluorescence microscopy, and on freshly isolated, single cell suspension of GBM tumor cells and GBM tumor cell lines, determined by based on flow cytometric analysis. Peripheral blood (PB) from patients with GBM, stimulated with mesothelin peptides and IL-2, IL-15 and IL-21, exhibited increased antigen-specific IFN-γ and TNF-α production. Anti-mesothelin directed T-cell responses could also be detected in tumor - infiltrating lymphocytes (TIL) isolated from GBM speciments. Furthermore, T cells cultured in the presence of IL-2, IL-15 and IL-21 displayed enhanced mesothelin-specific CD4+ and CD8+ subset proliferation, based on ELISA and flow cytometric readouts. Mesothelin-specific IgG antibodies as well as (shed) mature mesothelin protein were detected in plasma samples from patients with GBM by indirect ELISA. Finally yet importantly, we identified distinct immune recognition hotspots within the mature mesothelin component, defined by peptide-specific IFN-γ responses from peripheral T-cells from patients with GBM. Mesothelin may therefore qualify as a viable target for immunotherapeutic approaches for patients with GBM.
Highlights
Glioma represents the most severe form of a CNS malignancy arising from a mutation-driven pathological transformation of glia cells in the brain [1]
Our immunological data suggests that immune cells from patients with malignant primary glioma (i.e. Glioblastoma multiforme (GBM)) can strongly recognize and respond to cell surface-bound, mature mesothelin (GPI-anchored component) via cytokine production (IFN-γ, tumour necrosis factor alpha (TNF-α)), as well as antibody (IgG) production T cells from patients with GBM are able to expand dramatically in the presence of conditioning medium containing interleukin 2 (IL-2)/interleukin 15 (IL-15)/interleukin 21 (IL-21) as well as the mesothelin peptide pool - for antigenspecific cell activation
We We were not able to detect a ‘baseline’ immune reactivity directed to mesothelin peptides in T-cells obtained from peripheral blood from healthy donors, in line observed that with peripheral blood from healthy donors, there was no baseline induction of interferon gamma (IFN-γ) production in response to mesothelin peptides, in line with previous findings [21]
Summary
Glioma represents the most severe form of a CNS malignancy arising from a mutation-driven pathological transformation of glia cells in the brain [1]. Gliomas manifest in several histological forms, depending on stage of disease: A: diffuse or anaplastic astrocytoma (IDH-wildtype/-mutant/not otherwise specified (NOS)); OD: oligodendroglioma or anaplastic oligodendroglioma www.impactjournals.com/oncotarget (IDH-mutant and 1p/19q-codeleted/NOS); OA: oligoastrocytoma or anaplastic oligoastrocytoma (NOS); GBM: glioblastoma multiforme (IDH-wildtype/-mutant/ NOS) [2, 3]. The most malignant of these is GBM, representing 55% of all glioma diagnoses in humans. Low-grade astrocytomas can eventually progress to GBM, at which stage treatment options become limited. While mutant forms of the oncoprotein p53 as well as isocitrate dehydrogenase (IDH) are found in many low-grade gliomas [1, 2], mutations in epidermal growth factor receptor (EGFR) is present in 40% of GBM cases, the most common being the EGFRvIII mutation, which seen in approximately 25% of GBM [5]
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