Rocaglamide promotes the infiltration and antitumor immunity of NK cells by activating cGAS-STING signaling in non-small cell lung cancer.
Rocaglamide promotes the infiltration and antitumor immunity of NK cells by activating cGAS-STING signaling in non-small cell lung cancer.
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罗卡酰胺通过激活非小细胞肺癌中的cGAS-STING信号促进NK细胞的浸润和抗肿瘤免疫
DOI：
10.7150/ijbs.65019
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发表时间：
2022
影响因子：
9.2
通讯作者：
Zhu S
中科院分区：
文献类型：
--
作者：
Yan X;Yao C;Fang C;Han M;Gong C;Hu D;Shen W;Wang L;Li S;Zhu S
背景：由于实体瘤中肿瘤浸润不足，基于自然杀伤（NK）细胞的免疫治疗在临床上受到限制。我们先前已经发现天然产物罗格列胺（RocA）可以通过抑制自噬来增强NK细胞介导的对非小细胞肺癌（NSCLC）细胞的杀伤，并且自噬抑制已经显示出增加黑色素瘤中NK细胞肿瘤浸润。因此，我们假设RocA可以通过抑制自噬来增加NSCLC中NK细胞的浸润。研究方法：采用流式细胞术、RNA测序、实时荧光定量PCR、Western印迹分析和异种移植瘤模型等方法研究NK细胞的浸润情况及其机制。结果如下：RocA可显著增加NK细胞在NSCLC细胞中的浸润及CCL 5和CXCL 10的表达，抑制自噬/ULK 1、JNK和NF-κB不能逆转RocA的作用。然而，这种上调可以通过抑制TKB 1和STING来抑制。此外，RocA显著激活cGAS（环GMP-AMP合酶）-STING（干扰素基因刺激因子）信号通路，并且STING的抑制/耗尽消除了RocA诱导的CCL 5和CXCL 10的上调、NK细胞浸润和肿瘤消退。此外，RocA还可损伤线粒体DNA，促进线粒体DNA在胞质中的释放。mPTP抑制剂环孢菌素A可逆转RocA诱导的线粒体DNA胞浆释放。结论：RocA可通过靶向mtDNA激活cGAS-STING信号通路促进NK细胞浸润，但不能抑制自噬。综上所述，我们目前的研究结果表明，RocA是一种有效的cGAS-STING激动剂，在癌症免疫治疗中具有很好的潜力，特别是在基于NK细胞的免疫治疗中。
Background: Natural killer (NK) cell-based immunotherapy is clinically limited due to insufficient tumor infiltration in solid tumors. We have previously found that the natural product rocaglamide (RocA) can enhance NK cell-mediated killing of non-small cell lung cancer (NSCLC) cells by inhibiting autophagy, and autophagic inhibition has been shown to increase NK cell tumor infiltration in melanoma. Therefore, we hypothesized that RocA could increase NK cell infiltration in NSCLC by autophagy inhibition. Methods: Flow cytometry, RNA-sequencing, real-time PCR, Western blotting analysis, and xenograft tumor model were utilized to assess the infiltration of NK cells and the underlying mechanism. Results: RocA significantly increased the infiltration of NK cells and the expressions of CCL5 and CXCL10 in NSCLC cells, which could not be reversed by the inhibitions of autophagy/ULK1, JNK and NF-κB. However, such up-regulation could be suppressed by the inhibitions of TKB1 and STING. Furthermore, RocA dramatically activated the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway, and the inhibition/depletion of STING ablated the up-regulation of CCL5 and CXCL10, NK cell infiltration, and tumor regression induced by RocA. Besides, RocA damaged mitochondrial DNA (mtDNA) and promoted the cytoplasmic release of mtDNA. The mPTP inhibitor cyclosporin A could reverse RocA-induced cytoplasmic release of mtDNA. Conclusions: RocA could promote NK cell infiltration by activating cGAS-STING signaling via targeting mtDNA, but not by inhibiting autophagy. Taken together, our current findings suggested that RocA was a potent cGAS-STING agonist and had a promising potential in cancer immunotherapy, especially in NK cell-based immunotherapy.
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影响因子：
10.9
作者：
Kremer V;Ligtenberg MA;Zendehdel R;Seitz C;Duivenvoorden A;Wennerberg E;Colón E;Scherman-Plogell AH;Lundqvist A
通讯作者：
Lundqvist A
影响因子：
7.3
作者：
Klein K;He K;Younes AI;Barsoumian HB;Chen D;Ozgen T;Mosaffa S;Patel RR;Gu M;Novaes J;Narayanan A;Cortez MA;Welsh JW
通讯作者：
Welsh JW
罗卡酰胺通过抑制自噬增强 NK 细胞介导的非小细胞肺癌细胞杀伤作用
影响因子：
13.3
作者：
Yao, Chao;Ni, Zhongya;Zhu, Shiguo
通讯作者：
Zhu, Shiguo
影响因子：
5.8
作者：
Wennerberg, Erik;Kremer, Veronika;Lundqvist, Andreas
通讯作者：
Lundqvist, Andreas
影响因子：
5.6
作者：
Dong L;Gopalan V;Holland O;Neuzil J
通讯作者：
Neuzil J