ATM-ATR–dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype

Abstract

IntroductionNatural killer (NK) cells are present in the bloodstream, spleen, bone marrow, and in nonlymphoid organs and represent one of the main effectors of the immunosurveillance against tumors, by exerting 2 major effector functions, cytolysis of target cells and production of cytokines and chemokines. 1,2 The activity of NK cells depends on the interplay between inhibitory receptors for major histocompatibility complex (MHC) class I molecules and activating receptors, which operate in concert to induce the elimination of tumor cells. 3,4 Among the activating receptors particularly relevant for tumor cell recognition and killing is NKG2D, the receptor for the MHC I-related molecules MICA/B, and ULBPs (UL16-binding proteins), belonging to the C-type lectin-like receptor family. 3,[5][6][7] The NKG2D activating receptor is expressed not only on NK cells, but also on ␥␦ T cells, CD8 ϩ T cells, and a subset of CD4 ϩ T cells. The expression of NKG2D ligands is largely confined to virus-infected, tumor, and stressed cells. 7 To promote escape of tumors from NKG2D-mediated immunosurveillance, NKG2D ligands undergo proteolytic shedding. Soluble NKG2D ligands (NKG2DLs) have been shown to down-regulate the cell surface NKG2D expression on NK cells, resulting in impaired killing of tumor cells. 8,9 Another activating receptor involved in NK-cell-mediated tumor cell killing is DNAX accessory molecule-1 (DNAM-1), a transmembrane glycoprotein constitutively expressed on the majority of T cells, NK cells, and macrophages; its ligands are Nectin-2 (Nec-2, CD112) and the poliovirus receptor (PVR, CD155), which belong to the nectin/nectin-like family. 10-12 DNAM-1 ligands have been initially described as adhesion molecules mainly regulating trans-endothelial migration 13 and only recently they have been found on a variety of tumor cells. 12,14 Both DNAM-1 and NKG2D cooperate in the induction of NK-cell killing against tumor cells of different histotypes, including those of hematopoietic origin. 14,15 Similarly to the NKG2D ligands, soluble isoforms of PVR have also been found in human serum and in the culture supernatant of tumor cell lines, and their role in tumor immunoevasion has been considered. 12 It has recently been demonstrated that agents that produce a genotoxic stress or DNA-replication inhibitors up-regulate NKG2D ligand expression through the activation of ATM (ataxia telangiectasia mutated) and ATR (ATM-and Rad3-related) protein kinases on human fibroblasts and on mouse tumor cell lines, and enhance their destruction by NK cells. 16,17 Increased ligand expression is regulated by the activation of the DNA damage response (DDR). This is a cellular program devoted to the maintenance of genome integrity through the inhibition of cell cycle and activation of the DNA repair systems, or by the induction of apoptosis or a protracted cell-cycle arrest known as cellular senescence. 17,18 No information is so far available on the regulation of DNAM-1 ligand expression through the DDR pathway.Submitted August 11, 2008; acc...

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…9 In another study, low-dose chemotherapy triggered the expression of ligands for NKG2D and DNAM-1 on multiple myeloma, and promoted NK-cell degranulation against tumor. 117 Other Off-Target, Non-Immune-Based Effects of Chemotherapy Myelosuppression, which develops after cytotoxic chemotherapy, represents the major toxic side effect of cancer treatment, thus limiting its use. As the BM contains the most mitotically active cells in the organism, it becomes a preferential target for chemotherapy-induced cytotoxicity.…”

Cellular senescence impact on immune cell fate and function

“…NK cells then recognize these senescent cells through CD58‐ICAM1 binding (Chien et al ., 2011; Sagiv & Krizhanovsky, 2013). Furthermore, senescent cells express, in an ATM/ATR (ataxia telangiectasia mutated/Rad3‐related kinases)‐dependent manner, ligands for two NK cell activating receptors NKG2D and DNAM1 and secrete IL‐15, a cytokine that promotes NKG2D and DNAM1 expression in NK cells (Krizhanovsky et al ., 2008a; Soriani et al ., 2009). Following receptor activation, NK cells can then specifically induce the death of senescent cells through perforin release by exocytosis (Sedelies et al ., 2008; Sagiv et al ., 2013).…”

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

“…For instance, it has recently been shown that multiple myeloma senescent cells upregulate NK-and T-cells ligands. Expression of these ligands depends on the DNA damage response (Gasser and Raulet, 2006;Soriani et al, 2009). Notably, the DNA damage response also regulates the expression of death receptors in tumor cells, in response to ionizing radiation or chemotherapy (Raulet and Guerra, 2009).…”