OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy.
OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy.
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DOI：
10.1186/s12943-015-0307-3
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发表时间：
2015-02-15
期刊：
影响因子：
37.3
通讯作者：
Tominaga T
中科院分区：
文献类型：
--
作者：
Shibahara I;Saito R;Zhang R;Chonan M;Shoji T;Kanamori M;Sonoda Y;Kumabe T;Kanehira M;Kikuchi T;So T;Watanabe T;Takahashi H;Iwabuchi E;Tanaka Y;Shibahara Y;Sasano H;Ishii N;Tominaga T
胶质母细胞瘤是最恶性的人类脑肿瘤，预后很差；然而，一些患者表现出长期生存。共刺激分子OX40与其配体OX40L之间的相互作用产生t细胞活化的关键信号。这种相互作用的增强增强了抗肿瘤免疫。在本研究中，我们探讨了OX40信号是否参与了针对胶质母细胞瘤的抗肿瘤适应性免疫，并建立了治疗性抗胶质瘤疫苗治疗。肿瘤标本取自原发性胶质母细胞瘤（n = 110）和III级胶质瘤（n = 34）患者。采用定量聚合酶链反应（PCR）、流式细胞术和免疫组织化学方法分析OX40L在人胶质母细胞瘤标本中的表达。利用胶质母细胞瘤细胞系、小鼠胶质瘤模型和从人类受试者和小鼠中分离的T细胞，研究了OX40信号传导的功能后果。小鼠调节性T细胞在缺氧条件下（1.5% O2）进行细胞因子产生试验。OX40L mRNA在胶质母细胞瘤标本中表达，并且高水平表达与胶质母细胞瘤患者接受总体全切除后的无进展生存期延长相关。因此，OX40L蛋白在A172人胶质母细胞瘤细胞中表达，并在模拟胶质母细胞瘤微环境的缺氧条件下诱导其表达。值得注意的是，当人CD4 T细胞与表达OX40L的A172细胞在抗cd3包被板中共培养时，通过干扰素-γ的产生增加来判断，CD4 T细胞被激活。为了证实OX40L表达的生存优势，我们使用小鼠胶质瘤模型。携带被迫表达OX40L的胶质瘤细胞的小鼠在颅内移植后的观察期内没有死亡，而携带缺乏OX40L的胶质瘤细胞的小鼠全部死亡。在免疫系统受损的裸鼠中没有检测到OX40L的这种生存益处。此外，与全身腹腔注射相比，皮下注射OX40激动剂抗体和胶质瘤细胞裂解物可激发更强的抗肿瘤免疫，延长胶质瘤或胶质瘤起始细胞样细胞小鼠的存活时间。最后，OX40触发缺氧条件下培养的活化调节性T细胞，导致免疫抑制细胞因子IL10的诱导。胶质母细胞瘤通过OX40信号传导来指导免疫刺激或免疫抑制，这取决于其微环境。本文的在线版本（doi:10.1186/s12943-015-0307-3）包含补充材料，可供授权用户使用。
Glioblastoma is the most malignant human brain tumor and has a dismal prognosis; however, some patients show long-term survival. The interaction between the costimulatory molecule OX40 and its ligand OX40L generates key signals for T-cell activation. The augmentation of this interaction enhances antitumor immunity. In this present study, we explored whether OX40 signaling is responsible for antitumor adaptive immunity against glioblastoma and also established therapeutic antiglioma vaccination therapy. Tumor specimens were obtained from patients with primary glioblastoma (n = 110) and grade III glioma (n = 34). Quantitative polymerase chain reaction (PCR), flow cytometry, and immunohistochemistry were used to analyze OX40L expression in human glioblastoma specimens. Functional consequences of OX40 signaling were studied using glioblastoma cell lines, mouse models of glioma, and T cells isolated from human subjects and mice. Cytokine production assay with mouse regulatory T cells was conducted under hypoxic conditions (1.5% O2). OX40L mRNA was expressed in glioblastoma specimens and higher levels were associated with prolonged progression-free survival of patients with glioblastoma, who had undergone gross total resection. In this regard, OX40L protein was expressed in A172 human glioblastoma cells and its expression was induced under hypoxia, which mimics the microenvironment of glioblastoma. Notably, human CD4 T cells were activated when cocultured in anti-CD3-coated plates with A172 cells expressing OX40L, as judged by the increased production of interferon-γ. To confirm the survival advantage of OX40L expression, we then used mouse glioma models. Mice bearing glioma cells forced to express OX40L did not die during the observed period after intracranial transplantation, whereas all mice bearing glioma cells lacking OX40L died. Such a survival benefit of OX40L was not detected in nude mice with an impaired immune system. Moreover, compared with systemic intraperitoneal injection, the subcutaneous injection of the OX40 agonist antibody together with glioma cell lysates elicited stronger antitumor immunity and prolonged the survival of mice bearing glioma or glioma-initiating cell-like cells. Finally, OX40 triggering activated regulatory T cells cultured under hypoxia led to the induction of the immunosuppressive cytokine IL10. Glioblastoma directs immunostimulation or immunosuppression through OX40 signaling, depending on its microenvironment. The online version of this article (doi:10.1186/s12943-015-0307-3) contains supplementary material, which is available to authorized users.
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影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
OX40触发调节性T细胞抑制块并促进肿瘤排斥。
影响因子：
15.3
作者：
Piconese, Silvia;Valzasina, Barbara;Colombo, Mario P.
通讯作者：
Colombo, Mario P.
影响因子：
6.4
作者：
TANAKA, Y;INOI, T;HINUMA, Y
通讯作者：
HINUMA, Y
影响因子：
6.4
作者：
Grauer, Oliver M.;Nierkens, Stefan;Adema, Gosse J.
通讯作者：
Adema, Gosse J.
DOI：
10.4049/jimmunol.0901112
发表时间：
2009-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ruby CE;Yates MA;Hirschhorn-Cymerman D;Chlebeck P;Wolchok JD;Houghton AN;Offner H;Weinberg AD
通讯作者：
Weinberg AD