miR-150-5p-Containing Extracellular Vesicles Are a New Immunoregulator That Favor the Progression of Lung Cancer in Hypoxic Microenvironments by Altering the Phenotype of NK Cells

Wei-An Chang; Ming-Ju Tsai; Jen-Yu Hung; Kuan-Li Wu; Ying-Ming Tsai; Yung-Chi Huang; Chao-Yuan Chang; Pei-Hsun Tsai; Ya-Ling Hsu

doi:10.3390/cancers13246252

miR-150-5p-Containing Extracellular Vesicles Are a New Immunoregulator That Favor the Progression of Lung Cancer in Hypoxic Microenvironments by Altering the Phenotype of NK Cells

Cancers (Basel). 2021 Dec 13;13(24):6252. doi: 10.3390/cancers13246252.

Authors

Wei-An Chang^{1

2}, Ming-Ju Tsai^{1

2}, Jen-Yu Hung^{1

2

3}, Kuan-Li Wu^{1

3

4}, Ying-Ming Tsai^{1

2}, Yung-Chi Huang⁴, Chao-Yuan Chang^{2

4

5}, Pei-Hsun Tsai⁴, Ya-Ling Hsu^{4

6}

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
² School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
³ Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 801, Taiwan.
⁴ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁵ Department of Anatomy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁶ Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Abstract

Natural killer (NKs) cells are cytotoxic effector cells, which can modulate tumor metastasis according to their function; however, the role of NK cells in lung cancer has not been extensively investigated. In this study, we determined the functional profiles of NK cells in a hypoxic tumor microenvironment (TME) of lung cancer. We revealed CD226 downregulation and functional repression of NK cells after hypoxic lung cancer priming and we then investigated their interaction with extracellular vesicles (EVs) and miR-150-5p. We also found that NK cells from lung cancer patients had lower expression of CD226 on their surface and exhibited a pro-inflammatory, pro-angiogenic and tumorigenesis phenotype by expressing VEGF, CXCL1, CXCL8, S100A8 and MMPs. Moreover, inhibition of miR-150 improved tumor surveillance by reversing CD226 expression and subsequently reinstating cytotoxic NK cell activity in an animal model. Our study introduces a new scenario for the pro-inflammatory and pro-angiogenic activities of NK cells in the hypoxic TME in lung cancer.

Keywords: CD226; extracellular vesicles; lung cancer; miR-150-5p; nature killer cell.

Abstract

Grants and funding