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神经节苷脂抗原 G(D2)在尤文肉瘤中表面表达，允许 MHC 非依赖性免疫靶向。

The ganglioside antigen G(D2) is surface-expressed in Ewing sarcoma and allows for MHC-independent immune targeting.

机构信息

Department of Pediatric Haematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer-Campus 1, Muenster, 48149, Germany.

出版信息

Br J Cancer. 2012 Mar 13;106(6):1123-33. doi: 10.1038/bjc.2012.57. Epub 2012 Feb 28.

DOI:10.1038/bjc.2012.57
PMID:22374462
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3304425/
Abstract

BACKGROUND

Novel treatment strategies are needed to cure disseminated Ewing sarcoma. Primitive neuroectodermal features and a mesenchymal stem cell origin are both compatible with aberrant expression of the ganglioside antigen G(D2) and led us to explore G(D2) immune targeting in this cancer.

METHODS

We investigated G(D2) expression in Ewing sarcoma by immunofluorescence staining. We then assessed the antitumour activity of T cells expressing a chimeric antigen receptor specific for G(D2) against Ewing sarcoma in vitro and in vivo.

RESULTS

Surface G(D2) was detected in 10 out of 10 Ewing sarcoma cell lines and 3 out of 3 primary cell cultures. Moreover, diagnostic biopsies from 12 of 14 patients had uniform G(D2) expression. T cells specifically modified to express the G(D2)-specific chimeric receptor 14. G2a-28ζ efficiently interacted with Ewing sarcoma cells, resulting in antigen-specific secretion of cytokines. Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, G(D2)-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres. G(D2)-specific T cells further had activity against Ewing sarcoma xenografts.

CONCLUSION

G(D2) surface expression is a characteristic of Ewing sarcomas and provides a suitable target antigen for immunotherapeutic strategies to eradicate micrometastatic cells and prevent relapse in high-risk disease.

摘要

背景

需要新的治疗策略来治愈转移性尤文肉瘤。原始神经外胚层特征和间充质干细胞起源都与神经节苷脂抗原 G(D2)的异常表达兼容，这促使我们探索在这种癌症中 G(D2)免疫靶向治疗。

方法

我们通过免疫荧光染色研究了尤文肉瘤中 G(D2)的表达。然后，我们评估了针对 G(D2)的嵌合抗原受体表达的 T 细胞对体外和体内尤文肉瘤的抗肿瘤活性。

结果

在 10 个尤文肉瘤细胞系和 3 个原代细胞培养物中检测到表面 G(D2)，在 14 名患者中的 12 名患者的诊断性活检中均有均匀的 G(D2)表达。专门修饰以表达 G(D2-特异性嵌合受体 14.G2a-28ζ 的 T 细胞与尤文肉瘤细胞有效相互作用，导致抗原特异性细胞因子分泌。此外，来自健康供体和患者的嵌合受体基因修饰的 T 细胞对同种异体和自体尤文肉瘤均表现出强烈的 G(D2-特异性细胞毒性反应，包括作为多细胞、非锚定依赖性球体生长的肿瘤细胞。G(D2)-特异性 T 细胞对尤文肉瘤异种移植物也具有活性。

结论

G(D2)表面表达是尤文肉瘤的特征，为免疫治疗策略提供了合适的靶抗原，以根除微转移细胞并预防高危疾病的复发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/473cacf5bf23/bjc201257f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/7515dd15d146/bjc201257f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/8ea0edae3a83/bjc201257f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/149f515621fc/bjc201257f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/97261376628e/bjc201257f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/d6c6dde3b585/bjc201257f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/473cacf5bf23/bjc201257f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/7515dd15d146/bjc201257f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/8ea0edae3a83/bjc201257f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/149f515621fc/bjc201257f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/97261376628e/bjc201257f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/d6c6dde3b585/bjc201257f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5d3/3304425/473cacf5bf23/bjc201257f6.jpg

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