Rocaglamide promotes the infiltration and antitumor immunity of NK cells by activating cGAS-STING signaling in non-small cell lung cancer

作者：Xuewei Yan, Chao Yao, Fang Cheng, Min Ae Han, Chenyuan Gong, Dan Hu, Weiming Shen, Lixin Wang, Suyun Li, Shiguo Zhu · 发表于：International Journal of Biological Sciences · 年份：2021 · 被引用次数：96 · 研究领域：interferon and immune responses、Invertebrate Immune Response Mechanisms、Viral Infections and Vectors

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...