Exosomes Shuttle TREX1-Sensitive IFN-Stimulatory dsDNA from Irradiated Cancer Cells to DCs.
Exosomes Shuttle TREX1-Sensitive IFN-Stimulatory dsDNA from Irradiated Cancer Cells to DCs.
复制标题
DOI：
10.1158/2326-6066.cir-17-0581
复制
发表时间：
2018-08
影响因子：
10.1
通讯作者：
Demaria S
中科院分区：
文献类型：
--
作者：
Diamond JM;Vanpouille-Box C;Spada S;Rudqvist NP;Chapman JR;Ueberheide BM;Pilones KA;Sarfraz Y;Formenti SC;Demaria S
放射治疗(RT)在免疫原性剂量下导致癌细胞胞质双链DNA(DsDNA)积聚，通过cGAS/STIN途径激活I型干扰素(IFN-I)。肿瘤细胞来源的干扰素-I需要招募依赖于BATF3的树突状细胞(DC)到免疫原性低的肿瘤，并在免疫检查点阻断的情况下触发抗肿瘤T细胞反应。我们先前已经证明，核酸外切酶TREX1通过降解胞浆dsDNA来调节辐射免疫原性。肿瘤来源的DNA还可以激活CGAS/STING介导的DC在免疫原性肿瘤中产生干扰素-I。然而，癌细胞的DNA是如何转移到树突状细胞的细胞质中的，目前还不清楚。在这里，我们展示了由辐射的小鼠乳腺癌细胞(RT-TeX)产生的肿瘤衍生外体(TeX)将dsDNA转移到DC并刺激DC上调共刺激分子和依赖刺激性的干扰素-I的激活。在体内，在预防性接种实验中，RT-TeX激发肿瘤特异性CD8+T细胞反应，并保护小鼠免受肿瘤发展的影响，明显优于未经处理的癌细胞。我们证明RT-Tex的干扰素刺激dsDNA载量受亲本细胞中TREX1表达的调节。总体而言，这些结果确认RT-TeX是一种将干扰素刺激的dsDNA从受辐射的癌细胞转移到DC的机制。我们以前已经证明，TREX1的表达依赖于RT剂量大小。因此，这些数据对RT与免疫治疗的结合应用具有重要意义。
Radiotherapy (RT) used at immunogenic doses leads to accumulation of cytosolic double-stranded DNA (dsDNA) in cancer cells, which activates type I IFN (IFN-I) via the cGAS/STING pathway. Cancer cell-derived IFN-I is required to recruit BATF3-dependent dendritic cells (DCs) to poorly immunogenic tumors and trigger antitumor T-cell responses in combination with immune checkpoint blockade. We have previously demonstrated that the exonuclease TREX1 regulates radiation immunogenicity by degrading cytosolic dsDNA. Tumor-derived DNA can also activate cGAS/STING-mediated production of IFN-I by DCs infiltrating immunogenic tumors. However, how DNA from cancer cells is transferred to the cytoplasm of DCs remains unclear. Here, we showed that tumor-derived exosomes (TEX) produced by irradiated mouse breast cancer cells (RT-TEX) transfer dsDNA to DCs and stimulate DC upregulation of costimulatory molecules and STING-dependent activation of IFN-I. In vivo, RT-TEX elicited tumor-specific CD8+ T-cell responses and protected mice from tumor development significantly better than TEX from untreated cancer cells in a prophylactic vaccination experiment. We demonstrated that the IFN-stimulatory dsDNA cargo of RT-TEX is regulated by TREX1 expression in the parent cells. Overall, these results identify RT-TEX as a mechanism whereby IFN-stimulatory dsDNA is transferred from irradiated cancer cells to DCs. We have previously shown that the expression of TREX1 is dependent on the RT dose size. Thus, these data have important implications for the use of RT with immunotherapy.