Enhanced immunosuppression by therapy-exposed glioblastoma multiforme tumor cells
Enhanced immunosuppression by therapy-exposed glioblastoma multiforme tumor cells
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DOI：
10.1002/ijc.29309
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发表时间：
2015-06-01
影响因子：
6.4
通讯作者：
Hermans, Ian F.
中科院分区：
文献类型：
--
作者：
Authier, Astrid;Farrand, Kathryn J.;Hermans, Ian F.
多形性胶质母细胞瘤（GBM）是一种高度恶性的脑肿瘤，标准治疗后复发时间极短。由于复发性GBM通常对随后的放疗和化疗具有抗性，因此已提出免疫疗法作为替代治疗选择。虽然GBM诱导免疫抑制是公认的，但目前尚不清楚先前的常规治疗对GBM细胞调节免疫环境的能力有什么影响。在这项研究中，我们研究了免疫细胞和胶质瘤细胞之间的相互作用，已暴露于化疗或辐射在体外。我们证明了治疗的胶质瘤细胞比未治疗的细胞具有更强的免疫抑制作用，并且在动物模型中以更快的速度在体内形成肿瘤。体外处理的原代人GBM细胞的培养上清液也显示出增加抑制，这与辅助抑制细胞或T调节细胞的产生无关，并且可以直接作用于CD 4（+）和CD 8（+）T细胞增殖。虽然许多关键的免疫抑制性细胞因子在处理的细胞中过表达，包括IL-10、IL-6和GM-CSF，但通过抑制前列腺素E2可以减轻许多处理的GBM系中的抑制。这些结果首次揭示了常规疗法可以改变GBM肿瘤细胞中的免疫抑制途径，这一发现对免疫疗法与标准治疗的结合具有重要意义。由于复发性多形性胶质母细胞瘤（GBM）通常对放疗和化疗有抵抗力，因此已提出免疫治疗作为替代方案。不幸的是，GBM肿瘤和标准疗法都可以诱导免疫抑制。在这项研究中，作者询问这些疗法是否也可以增强GBM细胞调节免疫反应的能力。他们发现，经过处理的神经胶质瘤细胞确实比未经处理的细胞更具免疫抑制作用，并且在体内形成肿瘤的速度更快。这可能是免疫治疗与常规治疗时机的关键发现。
Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an extremely short time to relapse following standard treatment. Since recurrent GBM is often resistant to subsequent radiotherapy and chemotherapy, immunotherapy has been proposed as an alternative treatment option. Although it is well established that GBM induces immune suppression, it is currently unclear what impact prior conventional therapy has on the ability of GBM cells to modulate the immune environment. In this study, we investigated the interaction between immune cells and glioma cells that had been exposed to chemotherapy or irradiation in vitro. We demonstrate that treated glioma cells are more immunosuppressive than untreated cells and form tumors at a faster rate in vivo in an animal model. Cultured supernatant from in vitro-treated primary human GBM cells were also shown to increase suppression, which was independent of accessory suppressor cells or T regulatory cell generation, and could act directly on CD4(+) and CD8(+) T cell proliferation. While a number of key immunosuppressive cytokines were overexpressed in the treated cells, including IL-10, IL-6 and GM-CSF, suppression could be alleviated in a number of treated GBM lines by inhibition of prostaglandin E2. These results reveal for the first time that conventional therapies can alter immunosuppressive pathways in GBM tumor cells, a finding with important implications for the combination of immunotherapy with standard treatment.What's new? Since recurrent glioblastoma multiforme (GBM) is often resistant to radiotherapy and chemotherapy, immunotherapy has been proposed as an alternative. Unfortunately, both GBM tumors and standard therapies can induce immune suppression. In this study, the authors asked whether these therapies might also actually enhance the ability of GBM cells to modulate the immune response. They found that treated glioma cells are indeed more immunosuppressive than untreated cells, and form tumors at a faster rate in vivo. This may be a critical finding for the timing of immunotherapy with conventional treatment.