Int J Biol Sci 2022; 18(2):585-598. doi:10.7150/ijbs.65019 This issue

Research Paper

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

Xuewei Yan1,2*, Chao Yao1,2*, Cheng Fang1,2*, Min Han1, Chenyuan Gong1, Dan Hu3, Weiming Shen1,2, Lixin Wang1,2, Suyun Li4, Shiguo Zhu1,2✉

1. Center for Traditional Chinese Medicine and Immunology Research; School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd. Shanghai 201203, P. R. China.
2. Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd. Shanghai 201203, P. R. China.
3. School of Acupuncture, Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd. Shanghai 201203, P. R. China.
4. Department of Pathology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd. Shanghai 201203, P. R. China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Yan X, Yao C, Fang C, Han M, Gong C, Hu D, Shen W, Wang L, Li S, Zhu S. Rocaglamide promotes the infiltration and antitumor immunity of NK cells by activating cGAS-STING signaling in non-small cell lung cancer. Int J Biol Sci 2022; 18(2):585-598. doi:10.7150/ijbs.65019. Available from https://www.ijbs.com/v18p0585.htm

File import instruction

Abstract

Graphic abstract

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.

Keywords: Rocaglamide, NK cells, Non-small cell lung cancer, STING, Mitochondrial DNA