Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity.
Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity.
复制标题
DOI：
10.1016/j.celrep.2015.04.031
复制
发表时间：
2015-05-19
期刊：
影响因子：
8.8
通讯作者：
Gajewski TF
中科院分区：
文献类型：
--
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
自发肿瘤启动的T细胞引发依赖于肿瘤驻留树突状细胞产生IFN-β。基于最近的观察结果表明IFN-β表达依赖于宿主STING途径的激活，我们假设通过肿瘤内施用特异性激动剂直接参与STING将导致有效的抗肿瘤治疗。在使用小鼠STING激动剂DMXAA进行的原理验证研究显示出有效的治疗效果后，我们生成了激活所有人STING等位基因以及鼠STING的合成环状二核苷酸（CDN）衍生物。肿瘤内注射STING激动剂诱导小鼠中已建立肿瘤的显著消退，并产生能够排斥远处转移并提供长期免疫记忆的大量全身免疫应答。合成CDN作为癌症治疗剂具有高翻译潜力。
Spontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells. Based on recent observations indicating that IFN-β expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral administration of specific agonists would result in effective antitumor therapy. After proof-of-principle studies using the mouse STING agonist DMXAA showed a potent therapeutic effect, we generated synthetic cyclic dinucleotide (CDN) derivatives that activated all human STING alleles as well as murine STING. Intratumoral injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory. Synthetic CDNs have high translational potential as a cancer therapeutic.
登录
查看更多内容
影响因子：
7.4
作者：
Galon J;Pagès F;Marincola FM;Angell HK;Thurin M;Lugli A;Zlobec I;Berger A;Bifulco C;Botti G;Tatangelo F;Britten CM;Kreiter S;Chouchane L;Delrio P;Arndt H;Asslaber M;Maio M;Masucci GV;Mihm M;Vidal-Vanaclocha F;Allison JP;Gnjatic S;Hakansson L;Huber C;Singh-Jasuja H;Ottensmeier C;Zwierzina H;Laghi L;Grizzi F;Ohashi PS;Shaw PA;Clarke BA;Wouters BG;Kawakami Y;Hazama S;Okuno K;Wang E;O'Donnell-Tormey J;Lagorce C;Pawelec G;Nishimura MI;Hawkins R;Lapointe R;Lundqvist A;Khleif SN;Ogino S;Gibbs P;Waring P;Sato N;Torigoe T;Itoh K;Patel PS;Shukla SN;Palmqvist R;Nagtegaal ID;Wang Y;D'Arrigo C;Kopetz S;Sinicrope FA;Trinchieri G;Gajewski TF;Ascierto PA;Fox BA
通讯作者：
Fox BA
DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
11.4
作者：
Cavlar, Taner;Deimling, Tobias;Hornung, Veit
通讯作者：
Hornung, Veit
影响因子：
11.2
作者：
Blank, C;Brown, I;Gajewski, TF
通讯作者：
Gajewski, TF