Brother of the regulator of the imprinted site (BORIS) variant subfamily 6 is involved in cervical cancer stemness and can be a target of immunotherapy

Abstract

// Takuya Asano 1, 2 , Yoshihiko Hirohashi 1 , Toshihiko Torigoe 1 , Tasuku Mariya 1, 2 , Ryota Horibe 1, 3 , Takafumi Kuroda 1, 2 , Yuta Tabuchi 1, 2 , Hiroshi Saijo 1, 3 , Kazuyo Yasuda 1 , Masahito Mizuuchi 1, 2 , Akari Takahashi 1 , Hiroko Asanuma 4 , Tadashi Hasegawa 4 , Tsuyoshi Saito 2 , Noriyuki Sato 1 1 Departments of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan 2 Obsterics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan 3 Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan 4 Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan Correspondence to: Yoshihiko Hirohashi, e-mail: hirohash@sapmed.ac.jp Toshihiko Torigoe, e-mail: torigoe@sapmed.ac.jp Keywords: cancer stem cells, cervical cancer, CTL, BORIS, peptide vaccine Received: August 28, 2015      Accepted: January 19, 2016      Published: February 03, 2016 ABSTRACT Cervical cancer is a major cause of cancer death in females worldwide. Cervical cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are resistant to conventional radiotherapy and chemotherapy, and CSCs/CICs are thought to be responsible for recurrence. Eradication of CSCs/CICs is thus essential to cure cervical cancer. In this study, we isolated cervical CSCs/CICs by sphere culture, and we identified a cancer testis (CT) antigen, CTCFL/BORIS, that is expressed in cervical CSCs/CICs. BORIS has 23 mRNA isoform variants classified by 6 subfamilies (sfs), and they encode 17 different BORIS peptides. BORIS sf1 and sf4 are expressed in both CSCs/CICs and non-CSCs/CICs, whereas BORIS sf6 is expressed only in CSCs/CICs. Overexpression of BORIS sf6 in cervical cancer cells increased sphere formation and tumor-initiating ability compared with those in control cells, whereas overexpression of BORIS sf1 and BORIS sf4 resulted in only slight increases. Thus, BORIS sf6 is a cervical CSC/CIC-specific subfamily and has a role in the maintenance of cervical CSCs/CICs. BORIS sf6 contains a specific c-terminal domain (C34), and we identified a human leukocyte antigen (HLA)-A2-restricted antigenic peptide, BORIS C34_24(9) encoded by BORIS sf6. A BORIS C34_24(9)-specific cytotoxic T cell (CTL) clone showed cytotoxicity for BORIS sf6-overexpressing cervical cancer cells. Furthermore, the CTL clone significantly suppressed sphere formation of CaSki cells. Taken together, the results indicate that the CT antigen BORIS sf6 is specifically expressed in cervical CSCs/CICs, that BORIS sf6 has a role in the maintenance of CSCs/CICs, and that BORIS C34_24(9) peptide is a promising candidate for cervical CSC/CIC-targeting immunotherapy.