Home Life Sciences Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro
Article
Licensed
Unlicensed Requires Authentication

Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro

  • Maike Sauer , Katrin S. Reiners , Hinrich P. Hansen , Andreas Engert , Stephan Gasser and Elke Pogge von Strandmann EMAIL logo
Published/Copyright: June 20, 2013

Abstract

Evasion of apoptosis is a hallmark of cancer cells. Inhibitor of apoptosis proteins (IAPs) act as endogenous inhibitors of programmed cell death and are overexpressed in several tumors including Hodgkin lymphoma (HL). Preclinical studies indicate antitumor activity of IAP antagonists and clinical studies in hematological malignancies are underway. Here, we investigate the impact of the small molecule IAP antagonist LCL161 on HL cell lines. Although the antagonist caused rapid degradation of cIAP1 leading to TNFα secretion, LCL161 did not promote apoptosis significantly. However, LCL161 induced expression of MICA and MICB, ligands for the activating immune receptor NKG2D, and enhanced the susceptibility of HL cells to NKG2D-dependent lysis by NK cells. MICA/B upregulation was dependent on activation of the DNA damage response upon LCL161 treatment. Taken together, we demonstrate a novel link between IAP inhibition, DNA damage and immune recognition.


Corresponding author: Elke Pogge von Strandmann, Laboratory for Immunotherapy, Department of Internal Medicine I, University Hospital Cologne, D-50937 Cologne, Germany

We are deeply grateful to the Deutsche Krebshilfe (grant 109751 to EPvS) and the Deutsche Forschungsgemeinschaft (KFO286, Z4 to EPvS) for generous funding of this study. LCL161 was kindly provided by Novartis.

Conflict of interest statement

Author’s Conflict of interest disclosure: The authors report no potential conflicts of interest.

References

Akyurek, N., Ren, Y., Rassidakis, G.Z., Schlette, E.J., and Medeiros, L.J. (2006). Expression of inhibitor of apoptosis proteins in B-cell non-Hodgkin and Hodgkin lymphomas. Cancer 107, 1844–1851.10.1002/cncr.22219Search in Google Scholar PubMed

Armeanu, S., Bitzer, M., Lauer, U.M., Venturelli, S., Pathil, A., Krusch, M., Kaiser, S., Jobst, J., Smirnow, I., Wagner, A., et al. (2005). Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 65, 6321–6329.10.1158/0008-5472.CAN-04-4252Search in Google Scholar PubMed

Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J.H., Lanier, L.L., and Spies, T. (1999). Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729.10.1126/science.285.5428.727Search in Google Scholar PubMed

Boll, B., Eltaib, F., Reiners, K.S., von Tresckow, B., Tawadros, S., Simhadri, V.R., Burrows, F.J., Lundgren, K., Hansen, H.P., Engert, A., et al. (2009). Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin’s lymphoma cells for natural killer cell-mediated cytotoxicity. Clin. Cancer Res. 15, 5108–5116.10.1158/1078-0432.CCR-09-0213Search in Google Scholar PubMed

Boll, B., Hansen, H., Heuck, F., Reiners, K., Borchmann, P., Rothe, A., Engert, A., and Pogge von Strandmann, E. (2005). The fully human anti-CD30 antibody 5F11 activates NF-{kappa}B and sensitizes lymphoma cells to bortezomib-induced apoptosis. Blood 106, 1839–1842.10.1182/blood-2005-01-0427Search in Google Scholar PubMed

Chen, K.F., Lin, J.P., Shiau, C.W., Tai, W.T., Liu, C.Y., Yu, H.C., Chen, P.J., and Cheng, A.L. (2012). Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells. Biochem. Pharmacol. 84, 268–277.10.1016/j.bcp.2012.04.023Search in Google Scholar PubMed

Cheung, H.H., Mahoney,D.J., Lacasse, E.C., and Korneluk, R.G. (2009). Down-regulation of c-FLIP enhances death of cancer cells by smac mimetic compound. Cancer Res. 69, 7729–7738.10.1158/0008-5472.CAN-09-1794Search in Google Scholar PubMed

Cosman, D., Mullberg, J., Sutherland, C.L., Chin, W., Armitage, R., Fanslow, W., Kubin, M., and Chalupny, N.J. (2001). ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133.10.1016/S1074-7613(01)00095-4Search in Google Scholar PubMed

Darding, M. and Meier, P. (2012). IAPs: guardians of RIPK1. Cell Death Differ. 19, 58–66.10.1038/cdd.2011.163Search in Google Scholar PubMed PubMed Central

Deguine, J., Breart, B., Lemaître, F., and Bousso, P. (2012). Cutting edge: tumor-targeting antibodies enhance NKG2D-mediated NK cell cytotoxicity by stabilizing NK cell-tumor cell interactions. J. Immunol. 189, 5493–5497.10.4049/jimmunol.1202065Search in Google Scholar PubMed

Deveraux, Q. L. and Reed, J.C. (1999). IAP family proteins–suppressors of apoptosis. Genes Dev 13, 239–252.10.1101/gad.13.3.239Search in Google Scholar PubMed

Dutton, A., O’Neil, J.D., Milner, A.E., Reynolds, G.M., Starczynski, J., Crocker, J., Young, L.S., and Murray, P.G. (2004). Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin’s lymphoma cells from autonomous Fas-mediated death. Proc. Natl. Acad. Sci. USA 101, 6611–6616.10.1073/pnas.0400765101Search in Google Scholar PubMed PubMed Central

Gasser, S., Orsulic, S., and Raulet, D.H. (2005). The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190.10.1038/nature03884Search in Google Scholar PubMed PubMed Central

Gyrd-Hansen, M. and Meier, P. (2010). IAPs: from caspase inhibitors to modulators of NF-kB, inflammation and cancer. Nat. Rev. Cancer 10, 561–574.10.1038/nrc2889Search in Google Scholar PubMed

Hanahan, D. and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674.10.1016/j.cell.2011.02.013Search in Google Scholar PubMed

Horie, R., Higashihara, M., and Watanabe, T. (2003). Hodgkin’s lymphoma and CD30 signal transduction. Int. J. Hematol. 77, 37–47.10.1007/BF02982601Search in Google Scholar PubMed

Horie, R., Watanabe, T., Morishita, Y., Ito, K., Ishida, T., Kanegae, Y., Saito, I., Higashihara, M., Mori, S., Kadin, M.E., et al. (2002). Ligand-independent signaling by overexpressed CD30 drives NF-kB activation in Hodgkin-Reed-Sternberg cells. Oncogene 21, 2493–2503.10.1038/sj.onc.1205337Search in Google Scholar PubMed

Huang, B., Sikorski, R., Sampath, P., and Thorne, S.H. (2011). Modulation of NKG2D-ligand cell surface expression enhances immune cell therapy of cancer. J. Immunother. 34, 289–296.10.1097/CJI.0b013e31820e1b0dSearch in Google Scholar PubMed PubMed Central

Jayanthan, A., Howard, S.C., Trippett, T., Horton, T., Whitlock, J.A., Daisley, L., Lewis, V., and Narendran, A. (2009). Targeting the Bcl-2 family of proteins in Hodgkin lymphoma: in vitro cytotoxicity, target modulation and drug combination studies of the Bcl-2 homology 3 mimetic ABT-737. Leuk. Lymphoma 50, 1174–1182.10.1080/10428190902943069Search in Google Scholar PubMed

Jungnickel, B., Staratschek-Jox, A., Braeuninger, A., Spieker, T., Wolf, J., Diehl V., Hansmann M.-L., Rajewsky K., and Kueppers R. (2000). Clonal deleterious mutations in the IkBa gene in the malignant cells in Hodgkin’s lymphoma. J. Exp. Med. 191, 395–402.10.1084/jem.191.2.395Search in Google Scholar PubMed PubMed Central

Knights, A.J., Fucikova, J., Pasam, A., Koernig, S., and Cebon, J. (2013). Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy. Cancer Immunol. Immunother. 62, 321–335.10.1007/s00262-012-1342-1Search in Google Scholar PubMed

Li, L., Thomas, R.M., Suzuki, H., De Brabander, J.K., Wang, X., and Harran, P.G. (2004). A small molecule Smac mimic potentiates TRAIL- and TNFa-mediated cell death. Science 305, 1471–1474.10.1126/science.1098231Search in Google Scholar PubMed

Pich, C., Teiti, I., Rochaix, P., Mariamé, B., Couderc, B., Favre, G., and Tilkin-Mariamé, A.F. (2013). Statins reduce melanoma development and metastasis through MICA overexpression. Front. Immunol. 4, 62.10.3389/fimmu.2013.00062Search in Google Scholar PubMed PubMed Central

Scott, A.M., Wolchok, J.D., and Old, L.J. (2012). Antibody therapy of cancer. Nat. Rev. Cancer 12, 278–287.10.1038/nrc3236Search in Google Scholar PubMed

Servida, F., Lecis, D., Scavullo, C., Drago, C., Seneci, P., Carlo-Stella, C., Manzoni, L., Polli, E., Lambertenghi Deliliers, G., Delia. D., et al. (2011). Novel second mitochondria-derived activator of caspases (Smac) mimetic compounds sensitize human leukemic cell lines to conventional chemotherapeutic drug-induced and death receptor-mediated apoptosis. Invest. New Drugs 29, 1264–1275.10.1007/s10637-010-9475-6Search in Google Scholar PubMed

Soriani, A., Zingoni, A., Cerboni, C., Iannitto, M.L., Ricciardi, M.R., Di Gialleonardo, V., Cippitelli, M., Fionda, C., Petrucci, M.T., Guarini, A., et al. (2009). 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. Blood 113, 3503–3511.10.1182/blood-2008-08-173914Search in Google Scholar PubMed

Steidl, C., Connors, J.M., and Gascoyne, R.D. (2011). Molecular pathogenesis of Hodgkin’s lymphoma: increasing evidence of the importance of the microenvironment. J. Clin. Oncol. 2, 1812–1826.10.1200/JCO.2010.32.8401Search in Google Scholar PubMed

Strasser, A., Jost, P.J., and Nagata, S. (2009). The many roles of FAS receptor signaling in the immune system. Immunity 30, 180–192.10.1016/j.immuni.2009.01.001Search in Google Scholar PubMed PubMed Central

Varfolomeev, E., Blankenship, J.W., Wayson, S.M., Fedorova, A.V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J.N., Elliott, L.O., Wallweber, H.J., et al. (2007). IAP antagonists induce autoubiquitination of c-IAPs, NF-kB activation, and TNFa-dependent apoptosis. Cell 131, 669–681.10.1016/j.cell.2007.10.030Search in Google Scholar PubMed

Villa-Morales, M. and Fernandez-Piqueras, J. (2012). Targeting the Fas/FasL signaling pathway in cancer therapy. Expert Opin. Ther. Targets 16, 85–101.10.1517/14728222.2011.628937Search in Google Scholar PubMed

Vince, J.E., Wong, W.W., Khan, N., Feltham, R., Chau, D., Ahmed, A.U., Benetatos, C.A., Chunduru, S.K., Condon, S.M., McKinlay, M., et al. (2007). IAP antagonists target cIAP1 to induce TNFa-dependent apoptosis. Cell 131, 682–693.10.1016/j.cell.2007.10.037Search in Google Scholar PubMed

Received: 2013-4-19
Accepted: 2013-6-13
Published Online: 2013-06-20
Published in Print: 2013-10-01

©2013 by Walter de Gruyter Berlin Boston

Downloaded on 15.1.2026 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2013-0161/html?lang=en
Scroll to top button