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Received Nov 30, 2017; Revised Feb 7, 2018; Accepted Feb 18, 2018
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1. Introduction
Neuroblastoma (NB), the most aggressive extracranial solid tumor occurring in childhood, remains a challenging malignancy [1]. In spite of intensive therapeutic strategies based on surgery, radiotherapy, chemotherapy, and differentiating treatment with 13-cis-retinoic acid, NB outcome remains poor, with 3-year event-free survival lower than 40%. In particular, systemic chemotherapy administered to all patient groups (low, intermediate, and high risk), before surgery (neoadjuvant chemotherapy) or after surgery (adjuvant chemotherapy), represents the main treatment [2]. Of note, several genotoxic drugs, including those used in the treatment of NB, cause many side effects [3]. Thus, in order to minimize drug toxicity and to ameliorate the outcome and the lifestyle of the little patients affected by NB, further therapeutic options are needed.
The NK cell-based immunotherapy of cancer, including NB, is attracting more and more interest [4, 5]. The success of this approach depends on the susceptibility of NB cells to the cytolytic activity of allogeneic or autologous ex vivo expanded and activated, adoptively transferred, mature NK cells [6]. The antitumor efficacy of NK cells can be impaired by various immune-escape mechanisms adopted by high-risk NB cells. Thus, NB cells downregulate the expression of MHC class I molecules, rendering tumor cells resistant to T cell lysis [7], and display a reduced expression of ligands for NK cell-activating receptors whereby they become refractory also to the recognition and lysis operated by NK cells [8, 9]. Of note, the susceptibility of cancer cells to NK cell-mediated recognition and lysis is strictly dependent on the expression of ligands for NK cell-activating receptors [10]. Thus, the restoration of the expression levels of these ligands could represent a strategic approach to enhance NB susceptibility to the immune system.
The genotoxic effect typical of several anticancer agents induces DNA damage response (DDR), the pathway most extensively associated with the induction of the expression of ligands for NK cell-activating receptors [11–14]. Ataxia-telangiectasia mutated kinase (ATM) is recruited and activated by DNA double-strand breaks and, through the activation of Chk2 checkpoint kinase...