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科学家发现肿瘤免疫逃逸新机制

Date:Oct 16th, 2012 Views:5,244

  近日,中国科学院上海生命科学研究院生物化学与细胞生物学研究所刘小龙研究组在最新的研究中,揭示了转录因子AP-1在肿瘤免疫抑制中的作用及分子机制。相关研究成果日前在线发表于国际学术期刊美国《国家科学院院刊》。

  “肿瘤在发生发展过程中不断地与机体免疫系统相互作用。”刘小龙解释说,肿瘤细胞能够通过免疫编辑“进化”出一系列策略来躲避免疫系统的识别,甚至主动抑制免疫细胞对其的抑制和杀伤功能。然而,“作为获得性免疫重要组分,T细胞能否以及如何应答免疫编辑后的肿瘤生长目前仍然不清楚。”他说。

  在刘小龙研究员的指导下,博士研究生肖刚等研究发现,在肿瘤生长过程中,肿瘤浸润T细胞被激活并持续上调转录因子AP-1家族成员c-Fos的表达;通过转基因和基因敲除小鼠模型的研究发现,肿瘤浸润T细胞中c-Fos抑制T细胞抗肿瘤免疫功能。进一步研究揭示,c-Fos通过结合共抑制受体PD-1编码基因上游的顺式调控元件直接激活了T细胞中PD-1的表达,从而导致T细胞在富含PD-1配体的肿瘤微环境中失活。

  这一调控机制最终在该顺式元件定点突变的小鼠中得到了证实。突变小鼠的分析结果表明,AP-1介导的PD-1表达对于肿瘤免疫抑制、促进肿瘤生长具有关键调控作用。有关专家认为,该研究揭示了T细胞在肿瘤免疫应答过程中从最初激活响应肿瘤生长到最后丧失免疫功能这一变化的关键节点;促进了更好地理解T细胞在肿瘤免疫中的行为模式,同时也为揭示肿瘤免疫抑制机制并设计相关药物重塑癌症病人的抗肿瘤免疫功能提供新思路。

 

Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1

 

T cells play a critical role in tumor immunosurveillance by eliminating newly transformed somatic cells. However, tumor cell variants can escape from immunological control after immunoediting, leading to tumor progression. Whether and how T cells respond to tumor growth remain unclear. Here, we found that tumor-infiltrating T cells exhibited persistently up-regulated expression of the activator protein 1 (AP-1) subunit c-Fos during tumor progression. The ectopic expression of c-Fos in T cells exacerbated tumor growth, whereas the T-cell–specific deletion of c-Fos reduced tumor malignancy. This unexpected immunosuppressive effect of c-Fos was mediated through the induced expression of immune inhibitory receptor programmed death 1 (PD-1) via the direct binding of c-Fos to the AP-1–binding site in the Pdcd1 (gene encoding PD-1) promoter. A knock-in mutation of this binding site abrogated PD-1 induction, augmented antitumor T-cell function and repressed tumor growth. Taken together, these findings indicate that T-cell c-Fos subsequently induces PD-1 expression in response to tumor progression and that disrupting such induction is essential for repression of tumor growth.

 

原文链接:http://www.pnas.org/content/109/38/15419.abstract?sid=acb92906-c790-4cc1-abe2-1c4941bc8d2f
http://www.ncbi.nlm.nih.gov/pubmed/22949674

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