Radiotherapy-Induced Overexpression of Exosomal Mirna-378A-3P in Cancer Cells Limits Natural Killer Cells Cytotoxicity

Abstract

Aim: We here hypothesized that tumor-derived exosomal miRNA (TexomiR) released from irradiated tumors may play a role in the tumor cells escape to natural killer (NK) cells. Materials & methods: Our study included the use of different cancer cell lines, blood biopsies of xenograph mice model and patients treated with radiotherapy. Results: The irradiation of cancer cells promotes the TET2-mediated demethylation of miR-378 promoter, miR-378a-3p overexpression and its loading in exosomes, inducing the decrease of granzyme-B (GZMB) secretion by NK cells. An inverse correlation between TexomiR-378a-3p and GZMB was observed in murine and human blood samples. Conclusion: Our work identifies TexomiR-378a-3p as a molecular signature associated with the loss of NK cells cytotoxicity via the decrease of GZMB expression upon radiotherapy.

Keywords::

• DNA methylation
• exosomal miRNA
• glioblastoma
• granzyme B
• immune response
• miR-378
• NK cells
• radiotherapy
• resistance
• TET2

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2019-0193

Acknowledgments

The authors thank the Neurosurgery Department of the Hospital G. and R. Laënnec, CHU Nantes, and the Oncology Department of the ICO-Centre René Gauducheau, Nantes-Atlantique for the tumor samples.

Financial&competing interests disclosure

This work was supported by the leftover grants from the Ligue Nationale Contre le Cancer, Comité InterRégional Grand Ouest, département de Loire Atlantique, d’Ille et Vilaine, Vendée et Côte d’Armor (Subvention 2016, 2017 and 2018) and by a grant from Cancéropôle Grand-Ouest (ExomiR, AOS-2018, Région Pays de la Loire). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the leftover grants from the Ligue Nationale Contre le Cancer, Comité InterRégional Grand Ouest, département de Loire Atlantique, d’Ille et Vilaine, Vendée et Côte d’Armor (Subvention 2016, 2017 and 2018) and by a grant from Cancéropôle Grand-Ouest (ExomiR, AOS-2018, Région Pays de la Loire). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.