Induction of ATM/ATR pathway combined with Vγ2Vδ2 T cells enhances cytotoxicity of ovarian cancer cells

Many ovarian cancer cells express stress-related molecule MICA/B on their surface that is recognized by V gamma 2V delta 2 T cells through their NKG2D receptor, which is transmitted to downstream stress-signaling pathway. However, it is yet to be established how V gamma 2V delta 2 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 V gamma 2V delta 2 T cell-mediated cytotoxicity. Herein, we show that ATM/ATR pathway is modulated in ovarian cancer cells in the presence of V gamma 2V delta 2 T cells. Furthermore, downregulation of ATM pathway resulted downregulation of MICA, and reduced V gamma 2V delta 2 T cell-mediated cytotoxicity. Alternately, stimulating ATM pathway enhanced expression of MICA, and sensitized ovarian cancer cells for cytotoxic lysis by V gamma 2V delta 2 T cells. We further show that combining currently approved chemotherapeutic drugs, which induced ATM signal transduction, along with V gamma 2V delta 2 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 V gamma 2V delta 2 T cells for effectively treating resistant ovarian cancer cells. (C) 2014 Elsevier B.V. All rights reserved.