Liu Zhenjiang, Rao Martin, Poiret Thomas, Nava Silvia, Meng Qingda, von Landenberg Anna, Bartek Jiri, Xie Shanshan, Sinclair Georges, Peredo Inti, Dodoo Ernest, Maeurer Markus
Department of Laboratory Medicine, Division of Therapeutic Immunology, Karolinska Institutet, Stockholm, Sweden.
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Oncotarget. 2017 Aug 16;8(46):80208-80222. doi: 10.18632/oncotarget.20303. eCollection 2017 Oct 6.
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.
多形性胶质母细胞瘤（GBM）是最恶性的胶质瘤形式，尽管采用了标准治疗，其5年生存率仍低于3%。因此，有必要采用新型免疫疗法来改善GBM的治疗效果。已经确定了几个介导抗GBM细胞免疫反应的分子定义靶点。间皮素是一种肿瘤相关抗原（TAA），在几种不同组织学类型的实体瘤中表达。在此，我们报告间皮素在人类恶性胶质瘤中的免疫学意义。通过免疫荧光显微镜发现在人类GBM中存在成熟的、表面结合的间皮素蛋白表达，并且通过流式细胞术分析确定在新鲜分离的GBM肿瘤细胞单细胞悬液和GBM肿瘤细胞系中也存在该蛋白表达。来自GBM患者的外周血（PB）在用间皮素肽以及白细胞介素-2、白细胞介素-15和白细胞介素-21刺激后，表现出抗原特异性干扰素-γ和肿瘤坏死因子-α产生增加。在从GBM标本中分离出的肿瘤浸润淋巴细胞（TIL）中也能检测到抗间皮素定向的T细胞反应。此外，基于酶联免疫吸附测定（ELISA）和流式细胞术读数，在白细胞介素-2、白细胞介素-15和白细胞介素-21存在的情况下培养的T细胞显示出间皮素特异性CD4 +和CD8 +亚群增殖增强。通过间接ELISA在GBM患者的血浆样本中检测到间皮素特异性IgG抗体以及（脱落的）成熟间皮素蛋白。最后但同样重要的是，我们在成熟间皮素成分中确定了不同的免疫识别热点，这是由GBM患者外周T细胞的肽特异性干扰素-γ反应所定义的。因此，间皮素可能有资格成为GBM患者免疫治疗方法的可行靶点。
