Inhibition of Glycogen Synthase Kinase-3 Increases NKG2D Ligand MICA Expression and Sensitivity to NK Cell–Mediated Cytotoxicity in Multiple Myeloma Cells: Role of STAT3

Fionda, Cinzia; Malgarini, Giulia; Soriani, Alessandra; Zingoni, Alessandra; Cecere, Francesca; Iannitto, Maria Luisa; Ricciardi, Maria Rosaria; Verde, Federico; Petrucci, Maria Teresa; Santoni, Angela; Cippitelli, Marco

doi:10.4049/jimmunol.1201426

Cited by 63 publications

(62 citation statements)

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“…[32][33][34][35][36][37] To this regard, our group has demonstrated that a number of therapeutic drugs, including genotoxic agents, can boost the expression of NKG2D and DNAM-1 ligands on MM cells in vitro and ex vivo, and can enhance NK cell antitumor activity. 25,28,[38][39][40][41] Moreover, our findings also show that the enhanced expression of activating ligands on MM cells after the administration of genotoxic drugs such as doxorubicin and melphalan at doses that fail to induce apoptosis, is mediated by the DDR activation via ATM/ATR, and is associated with a drug-induced tumor cell senescent phenotype. 28,41 In this study, we explored the possibility to induce in vivo cellular senescence of tumor cells upon genotoxic drug treatment in a mouse model of MM resembling the human disease, and we evaluated the contribution of NK cells to the immune surveillance of MM cells in mice treated with low doses of melphalan.…”

Section: Introductionsupporting

confidence: 65%

Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

et al. 2016

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Recognition of tumor cells by the immune system is a key step in cancer eradication. Melphalan is an alkylating agent routinely used in the treatment of patients with multiple myeloma (MM), but at therapeutic doses it leads to an immunosuppressive state due to lymphopenia. Here, we used a mouse model of MM to investigate the ability of in vivo treatment with low doses of melphalan to modulate natural killer (NK) cell activity, which have been shown to play a major role in the control of MM growth. Melphalan treatment was able to enhance the surface expression of the stress-induced NKG2D ligands RAE-1 and MULT-1, and of the DNAM-1 ligand PVR (CD155) on MM cells, leading to better tumor cell recognition and killing by NK cells, as highlighted by NK cell increased degranulation triggered by melphalan-treated tumor cells. Remarkably, NK cell population was not affected by the melphalan dose used, but rather displayed activation features as indicated by CD107a and CD69 expression. Furthermore, we showed that low doses of melphalan fail to induce tumor cell apoptosis, but promote the in vivo establishment of a senescent tumor cell population, harboring high levels of the stressinduced ligands RAE-1 and PVR. Taken together our data support the concept of using chemotherapy in order to boost antitumor innate immune responses and report the possibility to induce cellular senescence of tumor cells in vivo.Abbreviations: BM, bone marrow; C 12 FDG, 5-dodecanoylaminofluorescein di-b-D-galactopyranoside; DDR, DNA damage response; DNAM-1, DNAX accessory molecule-1; IMiDs, immunomodulatory drugs; MFI, median fluorescence intensity; MM, multiple myeloma; NK cell, natural killer cell; NKG2D, natural-killer group 2 member D; PBS, phosphate-buffered saline; SA-b-Gal, senescence-associated b-galactosidase; SASP, senescence-associated secretory phenotype; X-Gal, 5-bromo-4-chloro-3-indolyl b-D-galactopyranoside

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Section: Introductionsupporting

confidence: 65%

Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

et al. 2016

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“…Enhancement of NK cell-mediated recognition of MM cells was reported by us and other investigators, showing increased surface expression of NKG2DLs on tumor cells following treatment with genotoxic agents (22) or with GSK3, HSP-90, and histone deacetylase inhibitors (23)(24)(25). Importantly, drug-induced expression of these ligands on MM cells was always associated with their ability to trigger increased NK cell degranulation in an NKG2D-dependent manner.…”

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confidence: 71%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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Genotoxic stress can promote antitumor NK cell responses by upregulating the surface expression of activating ligands on cancer cells. Moreover, a number of studies suggested a role for soluble NK group 2D ligands in the impairment of NK cell tumor recognition and killing. We investigated whether genotoxic stress could promote the release of NK group 2D ligands (MHC class I-related chain [MIC]A and MICB), as well as the molecular mechanisms underlying this event in human multiple myeloma (MM) cells. Our results show that genotoxic agents used in the therapy of MM (i.e., doxorubicin and melphalan) selectively affect the shedding of MIC molecules that are sensitive to proteolytic cleavage, whereas the release of the short MICA*008 allele, which is frequent in the white population, is not perturbed. In addition, we found that a disintegrin and metalloproteinase 10 expression is upregulated upon chemotherapeutic treatment both in patient-derived CD138(+)/CD38(+) plasma cells and in several MM cell lines, and we demonstrate a crucial role for this sheddase in the proteolytic cleavage of MIC by means of silencing and pharmacological inhibition. Interestingly, the drug-induced upregulation of a disintegrin and metalloproteinase 10 on MM cells is associated with a senescent phenotype and requires generation of reactive oxygen species. Moreover, the combined use of chemotherapeutic drugs and metalloproteinase inhibitors enhances NK cell-mediated recognition of MM cells, preserving MIC molecules on the cell surface and suggesting that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses

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“…Lentivirus production and infection of SKO-007(J3) cells were performed as described previously (20). Postinfection, cells were allowed to expand for 24 h and were then selected for puromycin (1 mg/ml) resistance.…”

Section: Virus Production and In Vitro Transductionmentioning

confidence: 99%

“…A pRL-CMV expression vector was cotransfected each time to normalize DNA uptake. Transfections were carried out using a 4D-Nucleofector System (Lonza) as described previously (20). Luciferase and Renilla activity were read using Dual-Luciferase Reporter Assay and the Glomax Multi Detection System (Promega) following the manufacturer's instructions.…”

Section: Real-time Pcrmentioning

confidence: 99%

Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

Soriani

Iannitto

Ricci

et al. 2014

The Journal of Immunology

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Increasing evidence indicates that cancer cell stress induced by chemotherapeutic agents promote antitumor immune responses and contribute to their full clinical efficacy. In this article, we identify the signaling events underlying chemotherapy-induced NKG2D and DNAM-1 ligand expression on multiple myeloma (MM) cells. Our findings indicate that sublethal doses of doxorubicin and melphalan initiate a DNA damage response (DDR) controlling ligand upregulation on MM cell lines and patient-derived malignant plasma cells in Chk1/2-dependent and p53-independent manner. Drug-induced MICA and PVR gene expression are transcriptionally regulated and involve DDR-dependent E2F1 transcription factor activity. We also describe the involvement of changes in the redox state in the control of DDR-dependent upregulation of ligand surface expression and gene transcriptional activity by using the antioxidant agent N-acetyl-l-cysteine. Finally, in accordance with much evidence indicating that DDR and oxidative stress are major determinants of cellular senescence, we found that redox-dependent DDR activation upon chemotherapeutic treatment is critical for MM cell entry in premature senescence and is required for the preferential ligand upregulation on senescent cells, which are preferentially killed by NK cells and trigger potent IFN-γ production. We propose immunogenic senescence as a mechanism that promotes the clearance of drug-treated tumor cells by innate effector lymphocytes, including NK cells.

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Inhibition of Glycogen Synthase Kinase-3 Increases NKG2D Ligand MICA Expression and Sensitivity to NK Cell–Mediated Cytotoxicity in Multiple Myeloma Cells: Role of STAT3

Cited by 63 publications

References 54 publications

Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

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