Immunobiological characterization of cancer stem cells isolated from glioblastoma patients.
Immunobiological characterization of cancer stem cells isolated from glioblastoma patients.
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DOI：
10.1158/1078-0432.ccr-09-2730
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发表时间：
2010-02-01
期刊：
影响因子：
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通讯作者：
Maccalli C
中科院分区：
文献类型：
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作者：
Di Tomaso T;Mazzoleni S;Wang E;Sovena G;Clavenna D;Franzin A;Mortini P;Ferrone S;Doglioni C;Marincola FM;Galli R;Parmiani G;Maccalli C
癌症干细胞（CSC）已经从人类肿瘤中分离出来，包括多形性胶质母细胞瘤（GBM）。本研究的目的是研究GBM CSCs的免疫生物学特性，并评估这些细胞是否适合进行免疫治疗。生成GBM CSC系及其胎牛血清（FBS）培养的非CSC对系，流式细胞术检测已知肿瘤抗原、MHC-I和MHC-II分子、抗原加工机械组分和NKG2D配体的表达。此外，通过细胞因子分泌（ELISPOT）或增殖（羧基荧光素二乙酸琥珀酰酯）试验，分别检测这些细胞系对自体或异体T淋巴细胞的免疫原性和免疫抑制作用。GBM CSC和FBS细胞系MHC-I、MHC-II和NKG2D配体分子分别呈弱阳性和弱阴性。抗原处理机制分子在两种细胞类型中也存在缺陷。IFNs或5-Aza脱氧胞苷可诱导大多数分子的上调，但在FBS中比在csc中更有效。由TH1和TH2亚群介导的患者t细胞反应可以在体外诱导对抗自体CSC。此外，CSC而非配对的FBS肿瘤细胞系抑制健康供体的t细胞增殖。值得注意的是，在一些免疫相关分子的蛋白质水平上，CSC和FBS之间也发现了差异基因特征。这些结果表明，与FBS系相比，GBM CSC的免疫原性较低，抑制活性较高。然而，免疫原性可以通过免疫调节来挽救，导致抗gbm T细胞介导的免疫反应。
Cancer stem cells (CSC) have been isolated from human tumors, including glioblastoma multiforme (GBM). The aims of this study were the immunobiological characterization of GBM CSCs and the assessment of whether these cells represent suitable targets for immunotherapy. GBM CSC lines and their fetal bovine serum (FBS)–cultured non-CSC pair lines were generated and examined by flow cytometry for expression of known tumor antigens, MHC-I and MHC-II molecules, antigen-processing machinery components, and NKG2D ligands. In addition, immunogenicity and immunosuppression of such cell lines for autologous or allogeneic T lymphocytes were tested by cytokine secretion (ELISPOT) or proliferation (carboxyfluorescein diacetate succinimidyl ester) assays, respectively. Both GBM CSC and FBS lines were weakly positive and negative for MHC-I, MHC-II, and NKG2D ligand molecules, respectively. Antigen-processing machinery molecules were also defective in both cell types. Upregulation of most molecules was induced by IFNs or 5-Aza deoxycytidine, although more efficiently in FBS than in CSCs. Patient T-cell responses, mediated by both TH1 and the TH2 subsets, against autologous CSC could be induced in vitro. In addition, CSC but not their paired FBS tumor lines inhibited T-cell proliferation of healthy donors. Notably, a differential gene signature that was confirmed at the protein levels for some immunologic-related molecules was also found between CSC and FBS lines. These results indicate lower immunogenicity and higher suppressive activity of GBM CSC compared with FBS lines. The immunogenicity, however, could be rescued by immune modulation leading to anti-GBM T cell–mediated immune response.