STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer.
STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer.
复制标题
DOI：
10.1038/s41416-018-0188-5
复制
发表时间：
2018-08
影响因子：
8.8
通讯作者：
Koti M
中科院分区：
文献类型：
--
作者：
Ghaffari A;Peterson N;Khalaj K;Vitkin N;Robinson A;Francis JA;Koti M
卵巢高级别浆液性癌（HGSC）主要在晚期诊断，主要采用减瘤手术治疗，然后进行铂/紫杉烷化疗。尽管某些患者从目前使用的化疗中获益显著，但仍有一些患者没有反应或反应持续时间不足。我们先前表明，来自化疗耐药患者的肿瘤具有免疫抑制的预先存在的肿瘤免疫微环境，I型干扰素（IFN 1）基因表达降低。在HGSC的ID 8-Trp 53 −/−免疫活性鼠模型中，评估了“干扰素基因的STimulator”激动剂与卡铂化疗和PD-1免疫检查点阻断疗法的组合的功效。用STING激动剂治疗导致腹水积累减少和肿瘤负荷降低。用卡铂、STING激动剂和抗PD-1抗体的组合治疗的小鼠的存活时间最长。肿瘤免疫转录组学分析显示，与溶媒对照相比，STING激动剂治疗小鼠的肿瘤中IFN应答、抗原呈递和MHC II基因更高。流式细胞术分析显示STING激动剂处理的小鼠中肿瘤内PD-1+和CD 69 + CD 62 L −、CD 8 + T细胞显著更高。这些发现将使旨在改善HGSC患者化疗反应和生存率的组合方法的临床试验的合理设计成为可能。
High-grade serous carcinoma (HGSC) of the ovary is predominantly diagnosed at late stages and primarily treated with debulking surgery followed by platinum/taxane-based chemotherapy. Although certain patients benefit significantly from currently used chemotherapy, there are patients who either do not respond or have an inadequate duration of response. We previously showed that tumours from chemoresistant patients have an immunosuppressed pre-existing tumour immune microenvironment with decreased expression of Type I Interferon (IFN1) genes. Efficacy of a ‘STimulator of INterferon Genes’ agonist was evaluated in combination with carboplatin chemotherapy and PD-1 immune checkpoint blockade therapy in the ID8-Trp53−/− immunocompetent murine model of HGSC. Treatment with STING agonist led to decreased ascites accumulation and decreased tumour burden. Survival of mice treated with a combination of carboplatin, STING agonist and anti-PD-1 antibody was the longest. Tumour immune transcriptomic profiling revealed higher IFN response, antigen presentation and MHC II genes in tumours from STING agonist-treated mice compared to vehicle controls. Flow cytometry analysis revealed significantly higher intra-tumoural PD-1+ and CD69+CD62L−, CD8+ T cells in STING agonist-treated mice. These findings will enable rational design of clinical trials aimed at combinatorial approaches to improve chemotherapy response and survival in HGSC patients.
登录
查看更多内容
影响因子：
--
作者：
Spranger S;Sivan A;Corrales L;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
8.8
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
通讯作者：
Gajewski TF
DOI：
10.1038/nrc4019
发表时间：
2015-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Bowtell DD;Böhm S;Ahmed AA;Aspuria PJ;Bast RC Jr;Beral V;Berek JS;Birrer MJ;Blagden S;Bookman MA;Brenton JD;Chiappinelli KB;Martins FC;Coukos G;Drapkin R;Edmondson R;Fotopoulou C;Gabra H;Galon J;Gourley C;Heong V;Huntsman DG;Iwanicki M;Karlan BY;Kaye A;Lengyel E;Levine DA;Lu KH;McNeish IA;Menon U;Narod SA;Nelson BH;Nephew KP;Pharoah P;Powell DJ Jr;Ramos P;Romero IL;Scott CL;Sood AK;Stronach EA;Balkwill FR
通讯作者：
Balkwill FR
影响因子：
17.1
作者：
Fu J;Kanne DB;Leong M;Glickman LH;McWhirter SM;Lemmens E;Mechette K;Leong JJ;Lauer P;Liu W;Sivick KE;Zeng Q;Soares KC;Zheng L;Portnoy DA;Woodward JJ;Pardoll DM;Dubensky TW Jr;Kim Y
通讯作者：
Kim Y
依赖于STING的胞质DNA感应促进了辐射诱导的I型干扰素依赖性抗肿瘤免疫。
影响因子：
32.4
作者：
Deng, Liufu;Liang, Hua;Xu, Meng;Yang, Xuanming;Burnette, Byron;Arina, Ainhoa;Li, Xiao-Dong;Mauceri, Helena;Beckett, Michael;Darga, Thomas;Huang, Xiaona;Gajewski, Thomas F.;Chen, Zhijian J.;Fu, Yang-Xin;Weichselbaum, Ralph R.
通讯作者：
Weichselbaum, Ralph R.