title: Induction of ATM/ATR pathway combined with Vγ2Vδ2 T cells enhances cytotoxicity of ovarian cancer cells.
abstract: Many ovarian cancer cells express stress-related molecule MICA/B on their surface that is recognized by Vγ2Vδ2 T cells through their NKG2D receptor, which is transmitted to downstream stress-signaling pathway. However, it is yet to be established how Vγ2Vδ2 T cell-mediated recognition of MICA/B signal is transmitted to downstream stress-related molecules. Identifying targeted molecules would be critical to develop a better therapy for ovarian cancer cells. It is well established that ATM/ATR signal transduction pathways, which is modulated by DNA damage, replication stress, and oxidative stress play central role in stress signaling pathway regulating cell cycle checkpoint and apoptosis. We investigated whether ATM/ATR and its down stream molecules affect Vγ2Vδ2 T cell-mediated cytotoxicity. Herein, we show that ATM/ATR pathway is modulated in ovarian cancer cells in the presence of Vγ2Vδ2 T cells. Furthermore, downregulation of ATM pathway resulted downregulation of MICA, and reduced Vγ2Vδ2 T cell-mediated cytotoxicity. Alternately, stimulating ATM pathway enhanced expression of MICA, and sensitized ovarian cancer cells for cytotoxic lysis by Vγ2Vδ2 T cells. We further show that combining currently approved chemotherapeutic drugs, which induced ATM signal transduction, along with Vγ2Vδ2 T cells enhanced cytotoxicity of resistant ovarian cancer cells. These findings indicate that ATM/ATR pathway plays an important role in tumor recognition, and drugs promoting ATM signaling pathway might be considered as a combination therapy together with Vγ2Vδ2 T cells for effectively treating resistant ovarian cancer cells.
authors.affiliation: Department of Internal Medicine, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA.
authors.forename: Manjusri
authors.initials: M
authors.lastname: Das
authors.affiliation: Department of Internal Medicine, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Kanji
authors.affiliation: Department of Internal Medicine, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA.
authors.forename: Reeva
authors.initials: R
authors.lastname: Aggarwal
authors.affiliation: Department of Internal Medicine, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Joseph
authors.affiliation: Department of Internal Medicine, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA.
authors.forename: Alo
authors.initials: A
authors.lastname: Ray
authors.affiliation: Department of Breast Program, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.affiliation: Department of Internal Medicine, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Pompili
authors.affiliation: Department of Internal Medicine, Wexner Medical Center at the Ohio State University, Columbus, OH 43210, USA; Innate Immunity, Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA. Electronic address: hiranmoy.das@osumc.edu.
authors.forename: Hiranmoy
authors.initials: H
authors.lastname: Das
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D017382:Reactive Oxygen Species; D016692:Receptors, Antigen, T-Cell, gamma-delta; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM/ATR pathway; Combination therapy; Cytotoxicity; MICA; Ovarian cancer; Vγ2Vδ2 T cells
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