小柯机器人

近日，美国纪念斯隆凯特林癌症中心Joan Massagué团队发现，STING抑制肺腺癌休眠转移的重新激活。该项研究成果于2023年3月29日在线发表在《自然》杂志上。

研究人员使用惰性肺腺癌转移的模型来确定了退出休眠期时免疫反应性的癌细胞内在决定因素。肿瘤内在免疫调节器的遗传筛选确定了干扰素基因的刺激器（STING）途径是转移性爆发的抑制因素。STING的活性在重新进入细胞周期的转移祖细胞中增加，并且在突破性转移中被STING启动子和增强子的高甲基化所抑制，或者在对TGFβ反应而重新进入休眠的细胞中被染色质抑制。STING在来自自发转移癌细胞中的表达抑制了它们的外生。

用STING激动剂对小鼠进行全身治疗，可以消除休眠期的转移，并以T细胞和自然杀伤细胞依赖的方式防止自发的爆发，这些效果需要癌细胞STING功能。因此，STING为防止休眠转移的进展提供了一个检查点，并为防止疾病复发提供了一个可治疗的策略。

据悉，转移经常由原发肿瘤明显成功治疗后仍处于休眠状态的散播癌细胞发展而来。这些细胞在免疫破坏性的静止状态和容易被免疫介导消除的增殖状态之间波动。人们对清除被唤醒的转移细胞以及如何治疗性地激活这一过程以消除患者的残余疾病知之甚少。

附：英文原文

Title: STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma

Author: Hu, Jing, Snchez-Rivera, Francisco J., Wang, Zhenghan, Johnson, Gabriela N., Ho, Yu-jui, Ganesh, Karuna, Umeda, Shigeaki, Gan, Siting, Mujal, Adriana M., Delconte, Rebecca B., Hampton, Jessica P., Zhao, Huiyong, Kottapalli, Sanjay, de Stanchina, Elisa, Iacobuzio-Donahue, Christine A., Peer, Dana, Lowe, Scott W., Sun, Joseph C., Massagu, Joan

Issue&Volume: 2023-03-29

Abstract: Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1,2,3,4,5,6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFβ. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner—these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.

DOI: 10.1038/s41586-023-05880-5

Source: https://www.nature.com/articles/s41586-023-05880-5

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