miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint

Shaohua Xu, Zhen Tao, Bo Hai, Huagen Liang, Ying Shi, Tao Wang, Wen Song, Yong Chen, Jun OuYang, Jinhong Chen, Fanfei Kong, Yishan Dong, Shi-Wen Jiang, Weiyong Li, Ping Wang, Zhiyong Yuan, Xiaoping Wan, Chenguang Wang, Wencheng Li, Xiaoping Zhang and Ke Chen ()
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Shaohua Xu: Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine
Zhen Tao: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer institute & Hospital, National Clinical Research Center of Cancer
Bo Hai: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Huagen Liang: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Ying Shi: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Tao Wang: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wen Song: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Yong Chen: Emergency Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Jun OuYang: Changzhou Maternal and Child Health Hospital Affiliated to Nanjing Medical University
Jinhong Chen: Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine
Fanfei Kong: Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine
Yishan Dong: Changzhou Maternal and Child Health Hospital Affiliated to Nanjing Medical University
Shi-Wen Jiang: Mercer University School of Medicine
Weiyong Li: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Ping Wang: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer institute & Hospital, National Clinical Research Center of Cancer
Zhiyong Yuan: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer institute & Hospital, National Clinical Research Center of Cancer
Xiaoping Wan: Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine
Chenguang Wang: Key Laboratory of Tianjin Radiation and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences
Wencheng Li: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Xiaoping Zhang: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Ke Chen: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Immune checkpoint blockade of the inhibitory immune receptors PD-L1, PD-1 and CTLA-4 has emerged as a successful treatment strategy for several advanced cancers. Here we demonstrate that miR-424(322) regulates the PD-L1/PD-1 and CD80/CTLA-4 pathways in chemoresistant ovarian cancer. miR-424(322) is inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. High levels of miR-424(322) in the tumours are positively correlated with the progression-free survival of ovarian cancer patients. Mechanistic investigations demonstrated that miR-424(322) inhibited PD-L1 and CD80 expression through direct binding to the 3′-untranslated region. Restoration of miR-424(322) expression reverses chemoresistance, which is accompanied by blockage of the PD-L1 immune checkpoint. The synergistic effect of chemotherapy and immunotherapy is associated with the proliferation of functional cytotoxic CD8+ T cells and the inhibition of myeloid-derived suppressive cells and regulatory T cells. Collectively, our data suggest a biological and functional interaction between PD-L1 and chemoresistance through the microRNA regulatory cascade.

Date: 2016
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DOI: 10.1038/ncomms11406

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