STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy.
STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy.
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DOI：
10.1038/s41556-020-0527-7
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发表时间：
2020-07
影响因子：
21.3
通讯作者：
Sahai E
中科院分区：
文献类型：
--
作者：
Arwert EN;Milford EL;Rullan A;Derzsi S;Hooper S;Kato T;Mansfield D;Melcher A;Harrington KJ;Sahai E
肿瘤微环境中的癌症相关成纤维细胞（CAF）发挥着不同的作用，并可以调节治疗反应。CAF的功能包括重塑细胞外基质（ECM），通过异型细胞-细胞接触促进癌细胞侵袭，以及产生多种炎症调节趋化因子和细胞因子。肿瘤内的炎症环境影响对许多疗法的反应，包括溶瘤病毒的功效，然而CAF在这种情况下的作用仍不清楚。此外，关于异型癌细胞-成纤维细胞接触触发的细胞信号传导，也不知道是什么激活成纤维细胞表达炎症介质。在这项研究中，我们发现癌细胞和CAFs之间的直接接触触发了成纤维细胞表达广泛的炎症调节因子。这是在细胞质从癌细胞转胞吞到成纤维细胞中导致STING和IRF 3介导的IFNB 1和其他细胞因子表达活化后开始的。然后，IFNB 1在癌细胞和基质成纤维细胞中驱动干扰素刺激的转录程序，并最终在体外和体内破坏溶瘤病毒的功效。此外，仅在基质成纤维细胞中靶向IRF 3恢复溶瘤HSV功能。
Cancer-associated fibroblasts (CAFs) within the tumour microenvironment perform diverse roles and can modulate therapy responses. CAF functions include remodelling the extracellular matrix (ECM), promoting cancer cell invasion via heterotypic cell-cell contacts, and producing a variety of inflammatory modulating chemokines and cytokines. The inflammatory environment within tumours influences responses to many therapies, including the efficacy of oncolytic viruses, however the role of CAFs in this context remains unclear. Further, little is known about the cell signalling triggered by heterotypic cancer cell - fibroblast contacts nor about what activates fibroblasts to express inflammatory mediators. In this study, we show that direct contact between cancer cells and CAFs triggers the expression of a wide range of inflammatory modulators by fibroblasts. This is initiated following transcytosis of cytoplasm from cancer cells into fibroblasts leading to the activation of STING and IRF3-mediated expression of IFNB1 and other cytokines. IFNB1 then drives interferon-stimulated transcriptional programmes in both cancer cells and stromal fibroblasts and ultimately undermines the efficacy of oncolytic viruses, both in vitro and in vivo. Further, targeting IRF3 solely in stromal fibroblasts restores oncolytic HSV function.
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影响因子：
78.5
作者：
Sahai, Erik;Astsaturov, Igor;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
21.3
作者：
Glück S;Guey B;Gulen MF;Wolter K;Kang TW;Schmacke NA;Bridgeman A;Rehwinkel J;Zender L;Ablasser A
通讯作者：
Ablasser A
影响因子：
16.6
作者：
Givel AM;Kieffer Y;Scholer-Dahirel A;Sirven P;Cardon M;Pelon F;Magagna I;Gentric G;Costa A;Bonneau C;Mieulet V;Vincent-Salomon A;Mechta-Grigoriou F
通讯作者：
Mechta-Grigoriou F
影响因子：
50.3
作者：
Costa, Ana;Kieffer, Yann;Mechta-Grigoriou, Fatima
通讯作者：
Mechta-Grigoriou, Fatima
影响因子：
8.8
作者：
Hassona, Y.;Cirillo, N.;Heesom, K.;Parkinson, E. K.;Prime, S. S.
通讯作者：
Prime, S. S.