Our results clearly demonstrate that inhibition of ATM
Our results clearly demonstrate that inhibition of ATM pathway activation results in resistance to Vγ2Vδ2 T cell-mediated cell death. Therefore, enhancing ATM activation along with Vγ2Vδ2 T cell treatment would promote the cytotoxicity of resistant ovarian cancer cells. To our knowledge, this is the first report of direct cross-talk of ATM signaling and Vγ2Vδ2 T cell treatment. The molecular mechanism of the inhibition of ATM pathway upon Vγ2Vδ2 T cell-mediated induction is not clear yet, but it is obvious that ATM activation is affected by inhibition of its phosphorylation. Taken together, we propose that ovarian cancer dorsomorphin inhibit ATM signaling pathway upon Vγ2Vδ2 T cell treatment, which in turn inhibit MICA surface expression, and reduce the cytotoxicity, resulting in resistance (Fig. 6). This also supports the mechanism that Vγ2Vδ2 T cells induce cytotoxicity through ATM signaling pathway. Based on our results, for the first time we tested a new combination therapy where drugs like etoposide or NCS could be considered as a combination therapeutic regimens in conjunction with Vγ2Vδ2 T cell-mediated immunotherapy for the treatment of ovarian cancers. Moreover, if CD8+ αβ T cells and NK cells function similar to the Vγ2Vδ2 T cells, then this combination therapy would be used to enhance cytotoxicity for these treatments. As resistance to chemotherapy is challenging in ovarian cancer and many other cancer types, we believe that this new therapeutic approach would highly benefit not only ovarian cancers, but also other cancer types.
Acknowledgements This work was supported in part by the National Institutes of Health grants, K01 AR054114 (NIAMS), SBIR R44 HL092706-01 (NHLBI), R21 CA143787 (NCI), Pelotonia Idea Award (OSUCCC), and the Ohio State University start-up fund. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Background Gynecologic (GYN) cancers, specifically cancers of the uterine cervix, uterine corpus, and ovary, represent a significant worldwide health problem with 1,085,948 new diagnoses and 493,713 deaths observed annually (globocan.iarc.fr). Primary cytoreductive surgery with platinum- and paclitaxel-based chemotherapy, either in the adjuvant or neoadjuvant setting, are the standards of care for ovarian cancer . Surgical staging plays a central role in endometrial cancer management, with platinum-based chemotherapy, radiation and/or hormonal therapy deployed in the adjuvant and salvage setting . Chemoradiation and ionizing radiation (IR) are standard treatments for cervical cancer with platinum-based combination chemotherapy used for patients with advanced and recurrent disease . Although response rates in these disease settings range from 34 to 77% , only 27%, 17% or 16% of women with advanced ovarian, endometrial or cervical cancer will be alive 5years after diagnosis, respectively . Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR) are two related phosphatidyl inositol 3-kinase-like protein (PIKK) kinases that act proximal in DNA damage response (DDR) pathways, differentially recognize genotoxic stress, and function to initiate cell cycle arrest and activate appropriate DNA repair mechanisms , . ATR becomes activated in response to arrested replication forks via its recruitment by replication protein A (RPA)-coated single-stranded (ss) DNA that involves topoisomerase binding protein 1 (TOPBP1) as well as the 9–1–1 complex , . The ATR effector kinase, checkpoint kinase 1 (Chk1), is activated by phosphorylation of Ser317 and Ser345 by ATR , . Chk1 can phosphorylate multiple G2/M checkpoint targets, including CDC25C and the tumor suppressor p53 , , . Canonical ATM activation occurs in response to DNA double strand breaks (DSBs) via the MRN (MRE11–RAD50–NBS1) complex , . The principle ATM effector kinase, checkpoint kinase 2 (Chk2), is activated through phosphorylation of Thr68 and plays significant roles in regulating cell cycle progression by phosphorylating myriad proteins, including p53 , .