9月4日,，國際學(xué)術(shù)期刊《美國科學(xué)院院刊》在線發(fā)表了中國科學(xué)院上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所劉小龍研究組的最新研究成果Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1，該研究揭示了轉(zhuǎn)錄因子AP-1在腫瘤免疫抑制中的作用及分子機(jī)制,。
腫瘤在發(fā)生發(fā)展過程中不斷地與機(jī)體免疫系統(tǒng)相互作用,。腫瘤細(xì)胞通過免疫編輯“進(jìn)化”出一系列策略來躲避免疫系統(tǒng)的識(shí)別甚至主動(dòng)抑制免疫細(xì)胞對(duì)腫瘤的抑制和殺傷功能,。作為獲得性免疫重要組分，T細(xì)胞能否以及如何應(yīng)答免疫編輯后的腫瘤生長目前仍然不清楚,。
劉小龍研究組的博士研究生肖剛等研究發(fā)現(xiàn),，在腫瘤生長過程中，腫瘤浸潤T細(xì)胞被激活并持續(xù)上調(diào)轉(zhuǎn)錄因子AP-1家族成員c-Fos的表達(dá),；通過轉(zhuǎn)基因和基因敲除小鼠模型的研究發(fā)現(xiàn),，腫瘤浸潤T細(xì)胞中c-Fos抑制T細(xì)胞抗腫瘤免疫功能。進(jìn)一步的研究揭示c-Fos通過結(jié)合共抑制受體PD-1編碼基因上游的順式調(diào)控元件直接激活了T細(xì)胞中PD-1的表達(dá),，從而導(dǎo)致T細(xì)胞在富含PD-1配體的腫瘤微環(huán)境中失活,。這一調(diào)控機(jī)制最終在該順式元件定點(diǎn)突變的小鼠中得到了證實(shí)，通過突變小鼠的分析結(jié)果表明AP-1介導(dǎo)的PD-1表達(dá)對(duì)于腫瘤免疫抑制,、促進(jìn)腫瘤生長具有關(guān)鍵調(diào)控作用,。該研究揭示了T細(xì)胞在腫瘤免疫應(yīng)答過程中從最初激活響應(yīng)腫瘤生長到最后喪失免疫功能這一變化的關(guān)鍵節(jié)點(diǎn)；促進(jìn)更好地理解T細(xì)胞在腫瘤免疫中的行為模式,，同時(shí)也為揭示腫瘤免疫抑制機(jī)制并設(shè)計(jì)相關(guān)藥物重塑癌癥病人的抗腫瘤免疫功能提供新思路,。
該研究得到葛高翔研究員的大力支持；研究工作獲得國家自然科學(xué)基金委,，科技部和上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
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
