Oncotarget

Research Papers: Immunology:

Mesothelin as a novel biomarker and immunotherapeutic target in human glioblastoma

Zhenjiang Liu, Martin Rao, Thomas Poiret, Silvia Nava, Qingda Meng, Anna von Landenberg, Jiri Bartek Jr., Shanshan Xie, Georges Sinclair, Inti Peredo, Ernest Dodoo, Markus Maeurer _

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Oncotarget. 2017; 8:80208-80222. https://doi.org/10.18632/oncotarget.20303

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Abstract

Liu Zhenjiang1, Martin Rao1, Thomas Poiret1,2, Silvia Nava1, Qingda Meng1, Anna von Landenberg1, Jiri Bartek Jr.3,4,5, Shanshan Xie6, Georges Sinclair3, Inti Peredo3, Ernest Dodoo3,*and Markus Maeurer1,2,*

1 Department of Laboratory Medicine, Division of Therapeutic Immunology, Karolinska Institutet, Stockholm, Sweden

2 Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden

3 Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden

4 Department of Clinical Neuroscience and Department of Medicine, Karolinska Institutet, Stockholm, Sweden

5 Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

6 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

* These authors have contributed equally to this work

Correspondence to:

Markus Maeurer, email:

Keywords: glioblastoma, mesothelin, T-cell response, interferon gamma, immunotherapy, Immunology and Microbiology Section, Immune response, Immunity

Received: February 25, 2017 Accepted: June 11, 2017 Published: August 16, 2017

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.


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