中研院Extrachromosomal telomere repeat DNA誘發抗癌反應: IFNβ production

中研院免疫機制新發現 癌症治療新契機 發稿時間：2017/11/28（中央社記者余曉涵台北28日電）中研院分生所助研究員陳律佑率領研究團隊發現，在癌細胞生成過程中，人體的「染色體外端粒DNA」會誘發細胞後天免疫反應，進而抑制常見於骨癌、兒童腦瘤等的ALT癌細胞成長。中央研究院今天舉行「發現癌細胞迴避免疫系統關鍵機制，有助發展癌症免疫治療」記者會。會中中研院分子生物研究所助研究員陳律佑表示，癌細胞可以分為兩大類，一種是有「端粒酶」的癌細胞，另一種則為沒有「端粒酶」的替代性延長端粒（ALT）癌細胞。陳律佑說，ALT癌細胞占所有腫瘤的10%至15%，尤其常見於兒童腦瘤、軟組織瘤及骨癌等癌症上面。他指出，這類型的癌症細胞中會充滿「染色體外端粒DNA」（簡稱ECTR），正常狀態中ECTR會活化細胞內負責偵測游離DNA的機制，進而釋放出抑制病毒的干擾素，而癌細胞中卻因為沒有啟動活化機制釋放干擾素，導致癌細胞增生。陳律佑表示，研究發現癌細胞中的ECTR沒有啟動活化機制釋放干擾素的原因是「STING蛋白」受到抑制；研究中也發現ALT癌細胞中功能缺失的「組蛋白H3.3」也是協助釋放干擾素的角色之一。陳律佑說，若可以同時修復STING蛋白跟組蛋白H3.3，就有機會恢復ECTR啟動活化機制釋放出干擾素的功能，抑制癌細胞，為癌症治療帶來新契機。陳律佑也認為，近期美國食品藥物管理局核可的溶瘤病毒免疫療法，可以應用在ALT癌症的治療，趁著免疫系統失能，以毒攻毒。中研院指出，此研究成果論文已經在11月6日發表於「自然-結構與分子生物學」（Nature Structural and Molecular Biology）期刊。1061128

Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway/ Nature Structural & Molecular Biology, 06 November 2017  Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNβ production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells. Notably, the ALT suppressors histone H3.3 and the ATRX–Daxx histone chaperone complex were also required to activate the DNA-sensing pathway. Collectively, our data suggest that the loss of the cGAS-STING pathway may be required to evade ECTR-induced anti-proliferation effects and permit ALT development, and this requirement may be exploited for treatments specific to cancers utilizing the ALT pathway.