The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas
The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas
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DOI：
10.1158/1078-0432.ccr-06-0593
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发表时间：
2006-08-01
影响因子：
11.5
通讯作者：
Formenti, Silvia C.
中科院分区：
文献类型：
--
作者：
Newcomb, Elizabeth W.;Demaria, Sandra;Formenti, Silvia C.
目的：高级别胶质瘤的治疗包括电离辐射治疗。胶质瘤细胞的高侵袭性阻碍了它们的根除，并导致了惨淡的预后。最近，我们报道了MHC-I类(MHC-I)产物在人和小鼠GL261胶质瘤侵袭性肿瘤细胞中的下调。在这里，我们验证了全脑放疗(WBRT)上调GL261肿瘤MHC-I表达，增强免疫治疗效果的假说。实验设计：采用流式细胞术和免疫组织化学方法分别在体外和体内分析GL261细胞MHC-I分子的表达。为了测试已建立的GL261胶质瘤对治疗的反应，将可测量(CT成像)脑肿瘤的小鼠随机分为四组，(A)不治疗，(B)两次4GyWBRT，(C)经照射的分泌粒细胞-巨噬细胞集落刺激因子的GL261细胞疫苗，或(D)WBRT和疫苗接种。结果：电离辐射剂量为4Gy时，GL261细胞表面MHC-I类分子表达上调。在体内，WBRT可诱导侵袭正常脑的胶质瘤细胞表达MHC-I类复合体的β2-微球蛋白轻链亚单位，并增加CD4+和CD8+T细胞的浸润。然而，通过WBRT或单独接种疫苗获得的生存优势微乎其微。相比之下，西医结合疫苗接种可将长期存活率提高到40%至80%，而其他组的长期存活率为0%至10%(P<；0.002)。结论：电离辐射联合外周免疫可成功治疗已建立的高级别胶质瘤。
Purpose: High-grade glioma treatment includes ionizing radiation therapy. The high invasiveness of glioma cells precludes their eradication and is responsible for the dismal prognosis. Recently, we reported the down-regulation of MHC class I (MHC-I) products in invading tumor cells in human and mouse GL261 gliomas. Here, we tested the hypothesis that whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261 tumors and enhances the effectiveness of immunotherapy.Experimental Design: MHC-I molecule expression on GL261 cells was analyzed in vitro and in vivo by flow cytometry and immunohistochemistry, respectively. To test the response of established GL261 gliomas to treatment, mice with measurable (at CT imaging) brain tumors were randomly assigned to four groups receiving (a) no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccination with irradiated GL261 cells secreting granulocyte-macrophage colony-stimulating factor, or (d) WBRT and vaccination. Endpoints were tumor response and survival.Results: An ionizing radiation dose of 4 Gy maximally up-regulated MHC-I molecules on GL261 cells in vitro. In vivo, WBRT induced the expression of the beta 2-microglobulin light chain subunit of the MHC class I complex on glioma cells invading normal brain and increased CD4+ and CD8+ T cell infiltration. However, the survival advantage obtained with WBRT or vaccination alone was minimal. In contrast, WBRT in combination with vaccination increased long-term survival to 40% to 80%, compared with 0% to 10% in the other groups (P < 0.002). Surviving animals showed antitumor immunity by rejecting challenge tumors.Conclusion: Ionizing radiation can be successfully combined with peripheral vaccination for the treatment of established high-grade gliomas.