Skip to main content

Advertisement

SpringerLink
Log in

The novel deubiquitinase inhibitor b-AP15 induces direct and NK cell-mediated antitumor effects in human mantle cell lymphoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The first therapeutic proteasome inhibitor bortezomib has clinical efficacy in mantle cell lymphoma (MCL) which resulted in its incorporation in treatment algorithms for this disease. Impairment of proteasomal function by bortezomib is mediated via inhibition of the 20S core particle. However, proteasome function can also be modified by targeting upstream components of the ubiquitin–proteasome system. Recently, b-AP15 has been identified as a small molecule achieving proteasome inhibition by targeting the deubiquitinase (DUB) activity of the 19S regulatory subunit and was found to inhibit cancer cell growth in preclinical analyses. In the present study, both direct antitumor effects and the possibility to induce natural killer group 2 member D ligands (NKG2DL) to reinforce NK cell immunity with b-AP15 were investigated to provide a rational basis for clinical evaluation of this novel DUB inhibitor in MCL. Treatment with b-AP15 resulted in reduced viability as well as induction of apoptosis in a time- and dose-dependent manner, which could be attributed to caspase activation in MCL cells. In addition, treatment with b-AP15 differentially induced NKG2DL expression and subsequent NK cell lysis of MCL cells. These results indicate that the DUB inhibitor b-AP15 displays substantial antitumor activity in human MCL and suggest that b-AP15 might be a novel therapeutic option in the treatment of MCL that warrants clinical investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ATCC:

American-Type Culture Collection

DSMZ:

German Collection of Microorganisms and Cell Cultures

DUB:

Deubiquitinase

FasL:

Fas ligand

FDA:

Food and Drug Administration

MCL:

Mantle cell lymphoma

MIC:

Major histocompatibility complex class I chain-related protein

NKG2D:

Natural killer group 2 member D

NKG2DL:

Natural killer group 2 member D ligands

PARP:

Poly-ADP ribose polymerase

PI:

Propidium iodide

RPL13:

Ribosomal protein L13

UCHL5:

Ubiquitin C-terminal hydrolase 5

ULBP:

UL16-binding protein

USP14:

Ubiquitin-specific peptidase 14

References

  1. Kropp KN, Strunz B, Kopp HG, Grünebach F, Kanz L, Salih HR, Rittig SM, Dörfel D (2015) The novel deubiquitinase (DUB) inhibitor b-AP15 induces apoptosis and inhibits proliferation in mantle cell lymphoma. Oncol Res Treatm 38(suppl 5):1–288. https://doi.org/10.1159/000439070 [abstract]

    Article  Google Scholar 

  2. Jares P, Colomer D, Campo E (2007) Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 7(10):750–762. https://doi.org/10.1038/nrc2230

    Article  PubMed  CAS  Google Scholar 

  3. Campo E, Rule S (2015) Mantle cell lymphoma: evolving management strategies. Blood 125(1):48–55. https://doi.org/10.1182/blood-2014-05-521898

    Article  PubMed  CAS  Google Scholar 

  4. Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, Szymczyk M, Bouabdallah R, Kneba M, Hallek M, Salles G, Feugier P, Ribrag V, Birkmann J, Forstpointner R, Haioun C, Hanel M, Casasnovas RO, Finke J, Peter N, Bouabdallah K, Sebban C, Fischer T, Duhrsen U, Metzner B, Maschmeyer G, Kanz L, Schmidt C, Delarue R, Brousse N, Klapper W, Macintyre E, Delfau-Larue MH, Pott C, Hiddemann W, Unterhalt M, Dreyling M, European Mantle Cell Lymphoma N (2016) Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 388(10044):565–575. https://doi.org/10.1016/S0140-6736(16)00739-X

    Article  PubMed  CAS  Google Scholar 

  5. Herrmann A, Hoster E, Zwingers T, Brittinger G, Engelhard M, Meusers P, Reiser M, Forstpointner R, Metzner B, Peter N, Wormann B, Trumper L, Pfreundschuh M, Einsele H, Hiddemann W, Unterhalt M, Dreyling M (2009) Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 27(4):511–518. https://doi.org/10.1200/JCO.2008.16.8435

    Article  PubMed  Google Scholar 

  6. Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, Pylypenko H, Verhoef G, Siritanaratkul N, Osmanov E, Alexeeva J, Pereira J, Drach J, Mayer J, Hong X, Okamoto R, Pei L, Rooney B, van de Velde H, Cavalli F, Investigators LYM (2015) Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med 372(10):944–953. https://doi.org/10.1056/NEJMoa1412096

    Article  PubMed  CAS  Google Scholar 

  7. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Stadtmauer EA, O’Connor OA, Shi H, Boral AL, Goy A (2006) Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24(30):4867–4874. https://doi.org/10.1200/JCO.2006.07.9665

    Article  PubMed  Google Scholar 

  8. Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A, Harousseau JL (2012) Proteasome inhibitors in multiple myeloma: 10 years later. Blood 120(5):947–959. https://doi.org/10.1182/blood-2012-04-403733

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Perez-Galan P, Mora-Jensen H, Weniger MA, Shaffer AL 3rd, Rizzatti EG, Chapman CM, Mo CC, Stennett LS, Rader C, Liu P, Raghavachari N, Stetler-Stevenson M, Yuan C, Pittaluga S, Maric I, Dunleavy KM, Wilson WH, Staudt LM, Wiestner A (2011) Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation. Blood 117(2):542–552. https://doi.org/10.1182/blood-2010-02-269514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Zhang L, Pham LV, Newberry KJ, Ou Z, Liang R, Qian J, Sun L, Blonska M, You Y, Yang J, Lin X, Rollo A, Tamayo AT, Lee J, Ford RJ, Zhao X, Kwak LW, Yi Q, Wang M (2013) In vitro and in vivo therapeutic efficacy of carfilzomib in mantle cell lymphoma: targeting the immunoproteasome. Mol Cancer Ther 12(11):2494–2504. https://doi.org/10.1158/1535-7163.MCT-13-0156

    Article  PubMed  CAS  Google Scholar 

  11. Crawford LJ, Walker B, Irvine AE (2011) Proteasome inhibitors in cancer therapy. J Cell Commun Signal 5(2):101–110. https://doi.org/10.1007/s12079-011-0121-7

    Article  PubMed  PubMed Central  Google Scholar 

  12. D’Arcy P, Brnjic S, Olofsson MH, Fryknas M, Lindsten K, De Cesare M, Perego P, Sadeghi B, Hassan M, Larsson R, Linder S (2011) Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med 17(12):1636–1640. https://doi.org/10.1038/nm.2536

    Article  PubMed  CAS  Google Scholar 

  13. Vogel RI, Coughlin K, Scotti A, Iizuka Y, Anchoori R, Roden RB, Marastoni M, Bazzaro M (2015) Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells. Oncotarget 6(6):4159–4170. https://doi.org/10.18632/oncotarget.2904

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chen X, Wu J, Chen Y, Ye D, Lei H, Xu H, Yang L, Wu Y, Gu W (2016) Ubiquitin-specific protease 14 regulates cell proliferation and apoptosis in oral squamous cell carcinoma. Int J Biochem Cell Biol 79:350–359. https://doi.org/10.1016/j.biocel.2016.08.038

    Article  PubMed  CAS  Google Scholar 

  15. Feng X, Holmlund T, Zheng C, Fadeel B (2014) Proapoptotic effects of the novel proteasome inhibitor b-AP15 on multiple myeloma cells and natural killer cells. Exp Hematol 42(3):172–182. https://doi.org/10.1016/j.exphem.2013.11.010

    Article  PubMed  CAS  Google Scholar 

  16. Tian Z, D’Arcy P, Wang X, Ray A, Tai YT, Hu Y, Carrasco RD, Richardson P, Linder S, Chauhan D, Anderson KC (2014) A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 123(5):706–716. https://doi.org/10.1182/blood-2013-05-500033

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Chitta K, Paulus A, Akhtar S, Blake MK, Caulfield TR, Novak AJ, Ansell SM, Advani P, Ailawadhi S, Sher T, Linder S, Chanan-Khan A (2015) Targeted inhibition of the deubiquitinating enzymes, USP14 and UCHL5, induces proteotoxic stress and apoptosis in Waldenstrom macroglobulinaemia tumour cells. Br J Haematol 169(3):377–390. https://doi.org/10.1111/bjh.13304

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wang X, D’Arcy P, Caulfield TR, Paulus A, Chitta K, Mohanty C, Gullbo J, Chanan-Khan A, Linder S (2015) Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chem Biol Drug Des 86(5):1036–1048. https://doi.org/10.1111/cbdd.12571

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Paulus A, Akhtar S, Caulfield TR, Samuel K, Yousaf H, Bashir Y, Paulus SM, Tran D, Hudec R, Cogen D, Jiang J, Edenfield B, Novak A, Ansell SM, Witzig T, Martin P, Coleman M, Roy V, Ailawadhi S, Chitta K, Linder S, Chanan-Khan A (2016) Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells. Blood Cancer J 6(11):e492. https://doi.org/10.1038/bcj.2016.93

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Shukla N, Somwar R, Smith RS, Ambati S, Munoz S, Merchant M, D’Arcy P, Wang X, Kobos R, Antczak C, Bhinder B, Shum D, Radu C, Yang G, Taylor BS, Ng CK, Weigelt B, Khodos I, de Stanchina E, Reis-Filho JS, Ouerfelli O, Linder S, Djaballah H, Ladanyi M (2016) Proteasome addiction defined in ewing sarcoma is effectively targeted by a novel class of 19S proteasome inhibitors. Cancer Res 76(15):4525–4534. https://doi.org/10.1158/0008-5472.can-16-1040

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Vogel RI, Pulver T, Heilmann W, Mooneyham A, Mullany S, Zhao X, Shahi M, Richter J, Klein M, Chen L, Ding R, Konecny G, Kommoss S, Winterhoff B, Ghebre R, Bazzaro M (2016) USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment. Oncotarget 7(21):30962–30976. https://doi.org/10.18632/oncotarget.8821

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wang X, Mazurkiewicz M, Hillert EK, Olofsson MH, Pierrou S, Hillertz P, Gullbo J, Selvaraju K, Paulus A, Akhtar S, Bossler F, Khan AC, Linder S, D’Arcy P (2016) The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Sci Rep 6:26979. https://doi.org/10.1038/srep26979

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Mazurkiewicz M, Hillert EK, Wang X, Pellegrini P, Olofsson MH, Selvaraju K, D’Arcy P, Linder S (2017) Acute lymphoblastic leukemia cells are sensitive to disturbances in protein homeostasis induced by proteasome deubiquitinase inhibition. Oncotarget 8(13):21115–21127. https://doi.org/10.18632/oncotarget.15501

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sarhan D, Wennerberg E, D’Arcy P, Gurajada D, Linder S, Lundqvist A (2013) A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells. Cancer Immunol Immunother 62(8):1359–1368. https://doi.org/10.1007/s00262-013-1439-1

    Article  PubMed  CAS  Google Scholar 

  25. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ (2011) Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29:235–271. https://doi.org/10.1146/annurev-immunol-031210-101324

    Article  PubMed  CAS  Google Scholar 

  26. Zamai L, Ahmad M, Bennett IM, Azzoni L, Alnemri ES, Perussia B (1998) Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J Exp Med 188(12):2375–2380

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Arase H, Arase N, Saito T (1995) Fas-mediated cytotoxicity by freshly isolated natural killer cells. J Exp Med 181(3):1235–1238

    Article  PubMed  CAS  Google Scholar 

  28. Caron G, Delneste Y, Aubry JP, Magistrelli G, Herbault N, Blaecke A, Meager A, Bonnefoy JY, Jeannin P (1999) Human NK cells constitutively express membrane TNF-alpha (mTNFalpha) and present mTNFalpha-dependent cytotoxic activity. Eur J Immunol 29(11):3588–3595

    Article  PubMed  CAS  Google Scholar 

  29. Topham NJ, Hewitt EW (2009) Natural killer cell cytotoxicity: how do they pull the trigger? Immunology 128(1):7–15. https://doi.org/10.1111/j.1365-2567.2009.03123.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274. https://doi.org/10.1146/annurev.immunol.23.021704.115526

    Article  PubMed  CAS  Google Scholar 

  31. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013) Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31:413–441. https://doi.org/10.1146/annurev-immunol-032712-095951

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Ullrich E, Koch J, Cerwenka A, Steinle A (2013) New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology 2(10):e26097. https://doi.org/10.4161/onci.26097

    Article  PubMed  PubMed Central  Google Scholar 

  33. Armeanu S, Krusch M, Baltz KM, Weiss TS, Smirnow I, Steinle A, Lauer UM, Bitzer M, Salih HR (2008) Direct and natural killer cell-mediated antitumor effects of low-dose bortezomib in hepatocellular carcinoma. Clin Cancer Res 14(11):3520–3528. https://doi.org/10.1158/1078-0432.CCR-07-4744

    Article  PubMed  CAS  Google Scholar 

  34. Vales-Gomez M, Chisholm SE, Cassady-Cain RL, Roda-Navarro P, Reyburn HT (2008) Selective induction of expression of a ligand for the NKG2D receptor by proteasome inhibitors. Cancer Res 68(5):1546–1554. https://doi.org/10.1158/0008-5472.CAN-07-2973

    Article  PubMed  CAS  Google Scholar 

  35. Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, Cippitelli M, Fionda C, Petrucci MT, Guarini A, Foa R, Santoni A (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(15):3503–3511. https://doi.org/10.1182/blood-2008-08-173914

    Article  PubMed  CAS  Google Scholar 

  36. Hilpert J, Grosse-Hovest L, Grunebach F, Buechele C, Nuebling T, Raum T, Steinle A, Salih HR (2012) Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses. J Immunol 189(3):1360–1371. https://doi.org/10.4049/jimmunol.1200796

    Article  PubMed  CAS  Google Scholar 

  37. Schmiedel BJ, Arelin V, Gruenebach F, Krusch M, Schmidt SM, Salih HR (2011) Azacytidine impairs NK cell reactivity while decitabine augments NK cell responsiveness toward stimulation. Int J Cancer 128(12):2911–2922. https://doi.org/10.1002/ijc.25635

    Article  PubMed  CAS  Google Scholar 

  38. Huang G, Li L, Zhou W (2015) USP14 activation promotes tumor progression in hepatocellular carcinoma. Oncol Rep 34(6):2917–2924. https://doi.org/10.3892/or.2015.4296

    Article  PubMed  CAS  Google Scholar 

  39. Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee HG, Steinle A (2003) Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 102(4):1389–1396. https://doi.org/10.1182/blood-2003-01-0019

    Article  PubMed  CAS  Google Scholar 

  40. Baltz KM, Krusch M, Bringmann A, Brossart P, Mayer F, Kloss M, Baessler T, Kumbier I, Peterfi A, Kupka S, Kroeber S, Menzel D, Radsak MP, Rammensee HG, Salih HR (2007) Cancer immunoediting by GITR (glucocorticoid-induced TNF-related protein) ligand in humans: NK cell/tumor cell interactions. FASEB J 21(10):2442–2454. https://doi.org/10.1096/fj.06-7724com

    Article  PubMed  CAS  Google Scholar 

  41. Butler JE, Moore MB, Presnell SR, Chan HW, Chalupny NJ, Lutz CT (2009) Proteasome regulation of ULBP1 transcription. J Immunol 182(10):6600–6609. https://doi.org/10.4049/jimmunol.0801214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Cai J, Xia X, Liao Y, Liu N, Guo Z, Chen J, Yang L, Long H, Yang Q, Zhang X, Xiao L, Wang X, Huang H, Liu J (2017) A novel deubiquitinase inhibitor b-AP15 triggers apoptosis in both androgen receptor-dependent and -independent prostate cancers. Oncotarget 8(38):63232–63246. https://doi.org/10.18632/oncotarget.18774

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lundqvist A, Abrams SI, Schrump DS, Alvarez G, Suffredini D, Berg M, Childs R (2006) Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res 66(14):7317–7325. https://doi.org/10.1158/0008-5472.CAN-06-0680

    Article  PubMed  CAS  Google Scholar 

  44. Hallett WH, Ames E, Motarjemi M, Barao I, Shanker A, Tamang DL, Sayers TJ, Hudig D, Murphy WJ (2008) Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. J Immunol 180(1):163–170

    Article  PubMed  CAS  Google Scholar 

  45. Yang G, Gao M, Zhang Y, Kong Y, Gao L, Tao Y, Han Y, Wu H, Meng X, Xu H, Zhan F, Wu X, Shi J (2015) Carfilzomib enhances natural killer cell-mediated lysis of myeloma linked with decreasing expression of HLA class I. Oncotarget 6(29):26982–26994. https://doi.org/10.18632/oncotarget.4831

    Article  PubMed  PubMed Central  Google Scholar 

  46. Oh YT, Deng L, Deng J, Sun SY (2017) The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5. Sci Rep 7(1):8027. https://doi.org/10.1038/s41598-017-08424-w

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wang X, Ottosson A, Ji C, Feng X, Nordenskjold M, Henter JI, Fadeel B, Zheng C (2009) Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity. Haematologica 94(4):470–478. https://doi.org/10.3324/haematol.13783

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ilona Hagelstein, Sylvia Klein, Melanie Kraft, and Elke Malenke for excellent technical assistance. Flow cytometry sample acquisition was done on shared instruments of the Flow Cytometry Core Facility Tübingen.

Funding

Susanne M. Rittig was supported by the European Social Fund in Baden-Württemberg.

Author information

Author notes

  1. Hans-Georg Kopp

    Present address: Departments of Molecular Oncology and Thoracic Oncology, Robert-Bosch-Hospital Stuttgart, Auerbachstr. 110, 70376, Stuttgart, Germany

  2. Susanne M. Rittig

    Present address: Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany

  3. Korbinian N. Kropp and Stefanie Maurer contributed equally.

Authors and Affiliations

  1. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner site Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany

    Korbinian N. Kropp, Stefanie Maurer, Kathrin Rothfelder, Bastian J. Schmied, Kim L. Clar, Moritz Schmidt, Benedikt Strunz, Helmut R. Salih & Daniela Dörfel

  2. Department of Medical Oncology, Hematology, Immunology, Rheumatology and Pulmology, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany

    Hans-Georg Kopp, Frank Grünebach, Susanne M. Rittig, Helmut R. Salih & Daniela Dörfel

  3. Institute for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Alexander Steinle

Authors
  1. Korbinian N. Kropp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefanie Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathrin Rothfelder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bastian J. Schmied
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kim L. Clar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Moritz Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Benedikt Strunz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hans-Georg Kopp
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alexander Steinle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Frank Grünebach
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Susanne M. Rittig
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Helmut R. Salih
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Daniela Dörfel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KNK and SM designed and performed the experiments and analyzed data. KR, BJS, KLC, MS, and BS performed experiments and analyzed data. KNK and DD wrote the initial draft of the manuscript. HGK, AS, and FG analyzed data. SMR and HRS revised the manuscript. DD designed and supervised the study.

Corresponding author

Correspondence to Daniela Dörfel.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

This study was approved by our institutional review board, the ethics committee of the Faculty of Medicine of the Eberhard Karls Universität Tübingen and of the University Hospital Tübingen (reference number 13/2007V) to be in accordance with the Declaration of Helsinki.

Informed consent

Buffy coat preparations were produced by the local blood bank after obtaining informed consent, in accordance with the principles of the Declaration of Helsinki and its later amendments. Peripheral blood samples from MCL patients were obtained after written informed consent.

Cell line authentication

MCL cells were purchased from DSMZ and ATCC for this project.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2045 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kropp, K.N., Maurer, S., Rothfelder, K. et al. The novel deubiquitinase inhibitor b-AP15 induces direct and NK cell-mediated antitumor effects in human mantle cell lymphoma. Cancer Immunol Immunother 67, 935–947 (2018). https://doi.org/10.1007/s00262-018-2151-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-018-2151-y

Keywords

Search

Navigation