Suppression of breast cancer cells resistant to a pure anti-estrogen with CAR-transduced natural killer cells

You-Zhe Lin; Chuan-Chun Lee; Der-Yang Cho; Yuan-Liang Wang; Chia-Yun Chen; Ching-Yu Weng; Shao-Chih Chiu; Mien-Chie Hung; Shao-Chun Wang

Suppression of breast cancer cells resistant to a pure anti-estrogen with CAR-transduced natural killer cells

Am J Cancer Res. 2021 Sep 15;11(9):4455-4469. eCollection 2021.

Authors

You-Zhe Lin¹, Chuan-Chun Lee², Der-Yang Cho^{1

3

4}, Yuan-Liang Wang^{1

2}, Chia-Yun Chen⁵, Ching-Yu Weng⁵, Shao-Chih Chiu^{1

3}, Mien-Chie Hung^{1

2

6

7}, Shao-Chun Wang^{1

2

6

8

7

9}

Affiliations

¹ Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University Taichung 40402, Taiwan.
² Center for Molecular Medicine, China Medical University Hospital Taichung 404332, Taiwan.
³ Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital Taichung 404332, Taiwan.
⁴ Department of Neurosurgery, China Medical University Hospital Taichung 404332, Taiwan.
⁵ Department of Medicine, College of Medicine, China Medical University Taichung 40402, Taiwan.
⁶ Research Center for Cancer Biology, China Medical University Taichung 40402, Taiwan.
⁷ Department of Biotechnology, Asia University Taichung 41354, Taiwan.
⁸ Cancer Biology and Drug Discovery Ph.D. Program, China Medical University Taichung 40402, Taiwan.
⁹ Department of Cancer Biology, University of Cincinnati Cincinnati, OH 45267, USA.

PMID: 34659898
PMCID: PMC8493389

Abstract

Anti-estrogens as hormone therapy are the mainstay treatment for estrogen receptor (ER)-positive breast cancer. ER inhibitors through modulating the transcriptional function of ER have been the frontline anti-estrogens to which refractory phenotype often developed in advanced cancer. The anti-estrogen fulvestrant is currently the only clinically approved pure anti-estrogen which causes ER degradation. However, resistance to fulvestrant still occurs and unfortunately it leaves few choices other than chemotherapy as the later-line treatments to fulvestrant-resistant tumors. Here we show that fulvestrant resistance was accompanied by increased expression of a number of innate immune response genes including the natural killer (NK) cell ligand B7-H6 on the cell surface. In an attempt to overcome the drug resistance phenotype, a NK-based molecular approach taking advantage of a chimeric antigen receptor (CAR) system targeting B7-H6 was established and tested in cells with acquired resistance to fulvestrant. The results demonstrate that the cell therapy approach as a single agent can effectively induce cell death of the resistant cancer cells which is enhanced by the increased expression of cell surface B7-H6. This approach departs from the traditional strategies of conquering anti-estrogen resistant breast cancer and offers a new avenue to eradicate hormone-refractory malignant solid tumors.

Keywords: B7-H6; Chimeric antigen receptor; NKp30/NCR3; anti-estrogen; breast cancer; cell therapy; estrogen receptor; fulvestrant; natural killer cell.