PNAS:刘小龙研究组揭示肿瘤免疫抑制新机制

9月4日，国际学术期刊《美国科学院院刊》在线发表了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的最新研究成果Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1，该研究揭示了转录因子AP-1在肿瘤免疫抑制中的作用及分子机制。

肿瘤在发生发展过程中不断地与机体免疫系统相互作用。肿瘤细胞通过免疫编辑“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肿瘤的抑制和杀伤功能。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。

刘小龙研究组的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。进一步的研究揭示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，通过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。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。

该研究得到葛高翔研究员的大力支持；研究工作获得国家自然科学基金委，科技部和上海市科委的经费支持。

doi: 10.1073/pnas.1206370109

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

Gang Xiao, Anqi Deng, Haifeng Liu, Gaoxiang Ge, and Xiaolong Liu

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-in filtra ti ng T cells exhibited persistently up-regulated expression of the activator pro-tein 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 un-expected 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 th e 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 expres-sion in response to tumor progression and that disrupting such in-duction is essential for repression of tumor growth