title: miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint.
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.
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer institute &Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hai
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
authors.forename: Huagen
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Song
authors.affiliation: Emergency Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Gynecology, Changzhou Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Changzhou 213003, China.
authors.forename: Jun
authors.initials: J
authors.lastname: OuYang
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
authors.forename: Fanfei
authors.initials: F
authors.lastname: Kong
authors.affiliation: Department of Gynecology, Changzhou Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Changzhou 213003, China.
authors.forename: Yishan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Biomedical Science, Mercer University School of Medicine, Savannah, Georgia 31404, USA.
authors.forename: Shi-Wen
authors.initials: SW
authors.lastname: Jiang
authors.affiliation: Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
authors.forename: Weiyong
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer institute &Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer institute &Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.affiliation: Key Laboratory of Tianjin Radiation and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College &Chinese Academy of Medical Sciences, Tianjin 300308, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C582672:MIRN322 microRNA, mouse; C554214:MIRN424 microrna, human; D035683:MicroRNAs