Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells.
Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells.
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DOI：
10.1126/sciimmunol.aal1713
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发表时间：
2017-05-19
影响因子：
24.8
通讯作者：
Deng L
中科院分区：
文献类型：
--
作者：
Dai P;Wang W;Yang N;Serna-Tamayo C;Ricca JM;Zamarin D;Shuman S;Merghoub T;Wolchok JD;Deng L
尽管靶向治疗和免疫治疗最近取得了进展，但晚期癌症仍然是治疗挑战。需要新的方法来改变肿瘤免疫抑制微环境，并促进识别肿瘤抗原，导致抗肿瘤免疫。痘病毒，如经修饰的安卡拉牛痘病毒（MVA），具有作为免疫抑制剂的潜力。在这里，我们表明，传统的树突状细胞（DC）与热灭活或紫外线灭活的MVA感染导致更高水平的IFN诱导比单独的MVA通过cGAS-STING细胞溶质DNA传感途径。瘤内注射灭活MVA（iMVA）是有效的，并在小鼠黑色素瘤和结肠癌模型中产生适应性抗肿瘤免疫。iMVA诱导的抗肿瘤治疗在STING或Batf 3缺陷型小鼠中的有效性低于野生型小鼠，表明细胞溶质DNA敏感和Batf 3依赖性CD 103 +/CD 8 α+ DC对于iMVA免疫治疗至关重要。肿瘤内递送iMVA和全身递送免疫检查点阻断剂的组合在双侧肿瘤植入模型以及单侧大型已建立肿瘤模型中产生协同抗肿瘤作用。我们的研究结果表明，灭活的牛痘病毒可用作人类癌症的免疫剂。
Advanced cancers remain a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immune-suppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses, such as modified vaccinia virus Ankara (MVA), have potential as immunotherapeutic agents. Here we show that infection of conventional dendritic cells (DCs) with heat-inactivated or UV-inactivated MVA leads to higher levels of IFN induction than MVA alone through the cGAS–STING cytosolic DNA-sensing pathway. Intratumoral injection of inactivated MVA (iMVA) was effective and generated adaptive antitumor immunity in murine melanoma and colon cancer models. iMVA-induced antitumor therapy was less effective in STING- or Batf3-deficient mice than in wild-type mice, indicating that both cytosolic DNA-sensing and Batf3-dependent CD103+/CD8α+ DCs are essential for iMVA immunotherapy. The combination of intratumoral delivery of iMVA and systemic delivery of immune checkpoint blockade generated synergistic antitumor effects in bilateral tumor implantation models as well as in a unilateral large established tumor model. Our results suggest that inactivated vaccinia virus could be used as a immunotherapeutic agent for human cancers.
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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：
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
影响因子：
28.2
作者：
Sánchez-Paulete AR;Cueto FJ;Martínez-López M;Labiano S;Morales-Kastresana A;Rodríguez-Ruiz ME;Jure-Kunkel M;Azpilikueta A;Aznar MA;Quetglas JI;Sancho D;Melero I
通讯作者：
Melero I
环状GMP-AMP合酶通过双链DNA诱导的寡聚化激活。
影响因子：
32.4
作者：
Li, Xin;Shu, Chang;Yi, Guanghui;Chaton, Catherine T.;Shelton, Catherine L.;Diao, Jiasheng;Zuo, Xiaobing;Kao, C. Cheng;Herr, Andrew B.;Li, Pingwei
通讯作者：
Li, Pingwei
DOI：
10.1084/jem.20101158
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diamond MS;Kinder M;Matsushita H;Mashayekhi M;Dunn GP;Archambault JM;Lee H;Arthur CD;White JM;Kalinke U;Murphy KM;Schreiber RD
通讯作者：
Schreiber RD