STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade.
STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade.
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DOI：
10.1126/scitranslmed.aaa4306
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发表时间：
2015-04-15
影响因子：
17.1
通讯作者：
Kim Y
中科院分区：
文献类型：
--
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
干扰素基因刺激因子（STING）是一种细胞溶质受体，可感知外源性和内源性细胞溶质环状二核苷酸（CDN），激活TBK 1/IRF 3（干扰素调节因子3）、NF-κB（核因子κB）和STAT 6（信号转导和转录激活因子6）信号传导途径，以诱导稳健的I型干扰素和促炎细胞因子应答。CDN配体与产生粒细胞-巨噬细胞集落刺激因子（GM-CSF）的细胞癌疫苗（称为STINGVAX）一起配制，该疫苗在已建立的癌症的多种治疗模型中表现出有效的体内抗肿瘤功效。我们发现，合理设计的合成CDN衍生物分子，包括具有Rp，Rp二硫代非对映异构体和非规范c[A（2′，5 ′）pA（3′，5 ′）p]磷酸桥结构的分子，增强了STINGVAX在小鼠中建立的癌症的多种侵袭性治疗模型中的抗肿瘤功效。抗肿瘤活性是STING依赖性的，并且与树突状细胞和肿瘤抗原特异性CD 8 + T细胞的活化增加相关。STINGVAX治疗小鼠的肿瘤显示出显著的PD-L1（程序性死亡配体1）上调，这与肿瘤浸润的CD 8 +IFNγ+ T细胞相关。当与PD-1（程序性死亡1）阻断剂联合使用时，STINGVAX可诱导对PD-1阻断剂无反应的可触及的免疫原性差的肿瘤消退。
Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing cellular cancer vaccines—termed STINGVAX—that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2′,5′)pA(3′,5′)p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen–specific CD8+ T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8+IFNγ+ T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.