3月9日，學(xué)術(shù)期刊Oncogene 在線發(fā)表了*上海生命科學(xué)研究院健康科學(xué)研究所時(shí)玉舫研究組題為Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity 的研究論文，揭示了組蛋白去乙?；敢种苿℉DACIs）通過抑制腫瘤浸潤(rùn)T細(xì)胞凋亡，提高抗腫瘤免疫反應(yīng)，能夠有效地抑制腫瘤生長(zhǎng)。

　　組蛋白去乙酰化酶（Histone deacelytase, HDAC）是嚴(yán)格調(diào)控組蛋白以及非組蛋白類的蛋白質(zhì)的去乙?；^程的重要酶類。這種酶能夠?qū)⒁阴；鶑馁嚢彼嵘弦瞥瑥亩淖內(nèi)旧|(zhì)和蛋白質(zhì)的結(jié)構(gòu)，進(jìn)而調(diào)節(jié)許多重要的細(xì)胞活動(dòng)，包括基因轉(zhuǎn)錄、信號(hào)轉(zhuǎn)導(dǎo)等。因此，組蛋白去乙?；笇?duì)保持乙?；姆€(wěn)態(tài)是非常重要的。它們的活性如果出現(xiàn)異常，就會(huì)導(dǎo)致基因表達(dá)等細(xì)胞活動(dòng)的異常，而這種現(xiàn)象在各種疾病中都有所發(fā)現(xiàn)。正因?yàn)榇耍M蛋白去乙?；傅囊种苿℉DAC Inhibitors, HDACIs）zui近幾年來被廣泛地研究，并且在包括神經(jīng)退行性疾病、自體免疫性疾病、急性移植物抗宿主病等眾多疾病中被視為具有潛在的治療效果，更重要的是，其在腫瘤的治療中顯示了良好的效果。但是，對(duì)于HDACIs治療腫瘤的具體機(jī)制研究并不深入，導(dǎo)致其在臨床上的使用受到了*的限制。

　　博士研究生曹楷等在研究員時(shí)玉舫的指導(dǎo)下，利用多種腫瘤模型，探討了HDACIs治療腫瘤的具體機(jī)制。前期研究發(fā)現(xiàn)，HDACIs對(duì)于腫瘤的治療作用是與免疫系統(tǒng)密切相關(guān)的，并且HDACIs被廣泛報(bào)道能夠影響免疫細(xì)胞的活性。由此，他們提出假設(shè)，HDACIs能夠通過影響腫瘤微環(huán)境中免疫細(xì)胞存活來發(fā)揮其*作用。

研究發(fā)現(xiàn)，HDACIs的確能夠顯著增加腫瘤微環(huán)境中免疫細(xì)胞的數(shù)量和活性，導(dǎo)致免疫細(xì)胞分泌的抗腫瘤因子大量增加，發(fā)揮顯著的抗腫瘤作用。進(jìn)一步研究發(fā)現(xiàn)，HDACIs是通過抑制由Fas-FasL通路介導(dǎo)的免疫細(xì)胞“激活誘導(dǎo)的細(xì)胞凋亡"（activation-induced cell death, AICD）過程來減少細(xì)胞死亡，從而增加免疫細(xì)胞數(shù)量。機(jī)制研究表明，HDACIs能夠通過抑制NFAT1-Egr2通路活性來抑制免疫細(xì)胞FasL分子的表達(dá)，從而抑制下游的凋亡信號(hào)激活。當(dāng)免疫細(xì)胞缺失FasL表達(dá)時(shí)，HDACIs的*效果也隨之消失，腫瘤微環(huán)境中的免疫細(xì)胞數(shù)量也沒有明顯變化。因此，此項(xiàng)研究證明了HDACIs通過抑制FasL介導(dǎo)的免疫細(xì)胞凋亡來發(fā)揮抗腫瘤作用，為癌癥治療提供了新的思路和方向。

　　該研究得到了國(guó)家*、*戰(zhàn)略性先導(dǎo)科技專項(xiàng)、*知識(shí)創(chuàng)新工程重大項(xiàng)目、國(guó)家自然科學(xué)基金委的資助。

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原文摘要：

Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity

The poor efficacy of the in vivo anti-tumor immune response has been partially attributed to ineffective T-cell responses mounted against the tumor. Fas-FasL-dependent activation-induced cell death (AICD) of T cells is believed to be a major contributor to compromised anti-tumor immunity. The molecular mechanisms of AICD are well-investigated, yet the possibility of regulating AICD for cancer therapy remains to be explored. In this study, we show that histone deacetylase inhibitors (HDACIs) can inhibit apoptosis of CD4+ T cells within the tumor, thereby enhancing anti-tumor immune responses and suppressing melanoma growth. This inhibitory effect is specific for AICD through suppressing NFAT1-regulated FasL expression on activated CD4+ T cells. In gld/gld mice with mutation in FasL, the beneficial effect of HDACIs on AICD of infiltrating CD4+ T cells is not seen, confirming the critical role of FasL regulation in the anti-tumor effect of HDACIs. Importantly, we found that the co-administration of HDACIs and anti-CTLA4 could further enhance the infiltration of CD4+ T cells and achieve a synergistic therapeutic effect on tumor. Therefore, our study demonstrates that the modulation of AICD of tumor-infiltrating CD4+ T cells using HDACIs can enhance anti-tumor immune responses, uncovering a novel mechanism underlying the anti-tumor effect of HDACIs.

來源：中科院