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Chronic lymphocytic leukemia

Immunomodulatory effects of pevonedistat, a NEDD8-activating enzyme inhibitor, in chronic lymphocytic leukemia-derived T cells

Leukemia volume 35, pages 156–168 (2021)Cite this article

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Abstract

Novel targeted agents used in therapy of lymphoid malignancies, such as inhibitors of B-cell receptor-associated kinases, are recognized to have complex immune-mediated effects. NEDD8-activating enzyme (NAE) has been identified as a tractable target in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. We and others have shown that pevonedistat (TAK-924), a small-molecule inhibitor of NAE, abrogates NF-κB signaling in malignant B cells. However, NF-κB pathway activity is indispensable in immune response, and T-cell function is altered in patients with CLL. Using T cells derived from patients with CLL, we demonstrate that although targeting NAE results in markedly differential expression of NF-κB-regulated genes and downregulation of interleukin (IL)-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased Treg differentiation and a shift toward TH1 phenotype, accompanied by increased interferon-γ production. These findings were recapitulated in vivo in immunocompetent mouse models. T cells exposed to pevonedistat in washout experiments, informed by its human pharmacokinetic profile, recover NAE activity, and maintain their response to T-cell receptor stimulation and cytotoxic potential. Our data shed light on the potential immune implications of targeting neddylation in CLL and lymphoid malignancies.

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Fig. 1: Targeting NAE attenuates TCR signaling.
Fig. 2: Pevonedistat influences T-cell activation and proliferation.
Fig. 3: Pevonedistat prevents differentiation of iTregs.
Fig. 4: Pevonedistat alters the polarization of CD4+ T cells.
Fig. 5: Pevonedistat modulates T-cell polarization in vivo.
Fig. 6: Pulse-exposure mimicking pevonedistat pharmacokinetics.
Fig. 7: Targeting NAE modulates T-cell subpopulations.

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References

  1. Kittai AS, Lunning M, Danilov AV. Relevance of prognostic factors in the era of targeted therapies in CLL. Curr Hematol Malig Rep. 2019;14:302–9.

    PubMed  Google Scholar 

  2. Shindiapina P, Brown JR, Danilov AV. A new hope: novel therapeutic approaches to treatment of chronic lymphocytic leukaemia with defects in TP53. Br J Haematol. 2014;167:149–61.

    PubMed  Google Scholar 

  3. Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Investig. 2017;127:3052–64.

    PubMed  PubMed Central  Google Scholar 

  4. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122:2539–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Lampson BL, Kasar SN, Matos TR, Morgan EA, Rassenti L, Davids MS, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128:195–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Ibrutinib blocks Btk-dependent NF-kB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood. 2018;132:1985–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Huang X, Dixit VM. Drugging the undruggables: exploring the ubiquitin system for drug development. Cell Res. 2016;26:484–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Milhollen MA, Traore T, Adams-Duffy J, Thomas MP, Berger AJ, Dang L, et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood. 2010;116:1515–23.

    CAS  PubMed  Google Scholar 

  9. Paiva C, Godbersen JC, Berger A, Brown JR, Danilov AV. Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents. Cell Death Dis. 2015;6:e1807.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Godbersen JC, Humphries LA, Danilova OV, Kebbekus PE, Brown JR, Eastman A, et al. The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-kappaB activation and induces apoptosis in chronic lymphocytic leukemia B cells. Clin Cancer Res. 2014;20:1576–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009;458:732–6.

    CAS  PubMed  Google Scholar 

  12. Godbersen JC, Humphries LA, Danilova OV, Kebbekus PE, Brown JR, Eastman A, et al. The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-κB activation and induces apoptosis in chronic lymphocytic leukemia B cells. Clin Cancer Res. 2014;20:1576–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Oh H, Ghosh S. NF-kappaB: roles and regulation in different CD4(+) T-cell subsets. Immunol Rev. 2013;252:41–51.

    PubMed  PubMed Central  Google Scholar 

  14. Paul S, Schaefer BC. A new look at T cell receptor signaling to nuclear factor-kappaB. Trends Immunol. 2013;34:269–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang Y, Shi CC, Zhang HP, Li GQ, Li SS. MLN4924 suppresses neddylation and induces cell cycle arrest, senescence, and apoptosis in human osteosarcoma. Oncotarget. 2016;7:45263–74.

    PubMed  PubMed Central  Google Scholar 

  16. Ruan Q, Chen YH. Nuclear factor-kappaB in immunity and inflammation: the Treg and Th17 connection. Adv Exp Med Biol. 2012;946:207–21.

    CAS  PubMed  Google Scholar 

  17. Long M, Park SG, Strickland I, Hayden MS, Ghosh S. Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity. 2009;31:921–31.

    CAS  PubMed  Google Scholar 

  18. Passerini L, Allan SE, Battaglia M, Di Nunzio S, Alstad AN, Levings MK, et al. STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25- effector T cells. Int Immunol. 2008;20:421–31.

    CAS  PubMed  Google Scholar 

  19. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–89.

    CAS  PubMed  Google Scholar 

  20. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.

    CAS  PubMed  Google Scholar 

  21. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146:772–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE. 2007;2007:cm8.

    PubMed  Google Scholar 

  23. Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989;169:59–72.

    CAS  PubMed  Google Scholar 

  24. Hsieh CS, Macatonia SE, O’Garra A, Murphy KM. T cell genetic background determines default T helper phenotype development in vitro. J Exp Med. 1995;181:713–21.

    CAS  PubMed  Google Scholar 

  25. Wagner TL, Ahonen CL, Couture AM, Gibson SJ, Miller RL, Smith RM, et al. Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R-848 and imiquimod. Cell Immunol. 1999;191:10–19.

    CAS  PubMed  Google Scholar 

  26. Vasilakos JP, Smith RM, Gibson SJ, Lindh JM, Pederson LK, Reiter MJ, et al. Adjuvant activities of immune response modifier R-848: comparison with CpG ODN. Cell Immunol. 2000;204:64–74.

    CAS  PubMed  Google Scholar 

  27. Shah JJ, Jakubowiak AJ, O’Connor OA, Orlowski RZ, Harvey RD, Smith MR, et al. Phase I study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma. Clin Cancer Res. 2016;22:34–43.

    CAS  PubMed  Google Scholar 

  28. Krackhardt AM, Harig S, Witzens M, Broderick R, Barrett P, Gribben JG. T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy. Blood. 2002;100:167–73.

    CAS  PubMed  Google Scholar 

  29. Maharaj K, Sahakian E, Pinilla-Ibarz J. Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia. Blood Adv. 2017;1:1867–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yin Q, Sivina M, Robins H, Yusko E, Vignali M, O’Brien S, et al. Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia. J Immunol. 2017;198:1740–7.

    CAS  PubMed  Google Scholar 

  31. Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Investig. 2008;118:2427–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ramsay AG, Evans R, Kiaii S, Svensson L, Hogg N, Gribben JG. Chronic lymphocytic leukemia cells induce defective LFA-1-directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide. Blood. 2013;121:2704–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Godbersen JC, Paiva C, Danilova OV, Berger A, Brown JR, Danilov AV. Targeting neddylation effectively antagonizes nuclear factor-kappaB in chronic lymphocytic leukemia B-cells. Leuk Lymphoma. 2015;56:1566–9.

    CAS  PubMed  Google Scholar 

  34. Ross SH, Cantrell DA. Signaling and function of interleukin-2 in T lymphocytes. Annu Rev Immunol. 2018;36:411–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Blank JL, Liu XJ, Cosmopoulos K, Bouck DC, Garcia K, Bernard H, et al. Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924. Cancer Res. 2013;73:225–34.

    CAS  PubMed  Google Scholar 

  36. Jin HS, Liao L, Park Y, Liu YC. Neddylation pathway regulates T-cell function by targeting an adaptor protein Shc and a protein kinase Erk signaling. Proc Natl Acad Sci USA. 2013;110:624–9.

    CAS  PubMed  Google Scholar 

  37. Friend SF, Peterson LK, Treacy E, Stefanski AL, Sosinowski T, Pennock ND, et al. The discovery of a reciprocal relationship between tyrosine-kinase signaling and cullin neddylation. PLoS ONE. 2013;8:e75200.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Fan MY, Low JS, Tanimine N, Finn KK, Priyadharshini B, Germana SK, et al. Differential roles of IL-2 signaling in developing versus mature tregs. Cell Rep. 2018;25:1204–.e1204.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kitz A, Dominguez-Villar M. Molecular mechanisms underlying Th1-like Treg generation and function. Cell Mol Life Sci. 2017;74:4059–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Shen E, Zhao K, Wu C, Yang B. The suppressive effect of CD25+Treg cells on Th1 differentiation requires cell-cell contact partially via TGF-beta production. Cell Biol Int. 2011;35:705–12.

    CAS  PubMed  Google Scholar 

  41. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol. 2009;10:595–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Cote-Sierra J, Foucras G, Guo L, Chiodetti L, Young HA, Hu-Li J, et al. Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci USA. 2004;101:3880–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Brusa D, Serra S, Coscia M, Rossi D, D’Arena G, Laurenti L, et al. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013;98:953–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. DiLillo DJ, Weinberg JB, Yoshizaki A, Horikawa M, Bryant JM, Iwata Y, et al. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function. Leukemia. 2013;27:170–82.

    CAS  PubMed  Google Scholar 

  45. Francis S, Karanth M, Pratt G, Starczynski J, Hooper L, Fegan C, et al. The effect of immunoglobulin VH gene mutation status and other prognostic factors on the incidence of major infections in patients with chronic lymphocytic leukemia. Cancer. 2006;107:1023–33.

    CAS  PubMed  Google Scholar 

  46. Riches JC, Gribben JG. Understanding the immunodeficiency in chronic lymphocytic leukemia: potential clinical implications. Hematol Oncol Clin N Am. 2013;27:207–35.

    Google Scholar 

  47. Forconi F, Moss P. Perturbation of the normal immune system in patients with CLL. Blood. 2015;126:573–81.

    CAS  PubMed  Google Scholar 

  48. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121:1612–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gorgun G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Investig. 2005;115:1797–805.

    PubMed  PubMed Central  Google Scholar 

  50. Lee GR. The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci. 2018;19:E730.

    PubMed  Google Scholar 

  51. Swords RT, Coutre S, Maris MB, Zeidner JF, Foran JM, Cruz J, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018;131:1415–24.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the Leukemia & Lymphoma Society Translational Research Program Award #6542-18 (to AVD) and by a grant from Takeda Oncology. AVD is a Leukemia and Lymphoma Society Scholar in Clinical Research (#2319-19).

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Authors and Affiliations

  1. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

    Scott Best, Vi Lam, Tingting Liu, Nur Bruss, Adam Kittai, Olga V. Danilova, Evan F. Lind & Alexey V. Danilov

  2. University of Portland, Portland, OR, USA

    Susan Murray

  3. Millennium Pharmaceuticals, Inc., Cambridge, MA, USA

    Allison Berger

  4. Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA

    Nathan D. Pennock

  5. City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA, 91010, USA

    Alexey V. Danilov

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AVD has received research funding from Astra Zeneca, Gilead Sciences, Genentech, Aptose Biosciences, MEI Pharma, Takeda Oncology, Bayer Oncology, Verastem Oncology, and Bristol-Meyers-Squibb; honoraria from Astra Zeneca, Celgene, Curis, Genentech, Gilead Sciences, Janssen Oncology, Pharmacyclics, Seattle Genetics, TG Therapeutics, and Verastem Oncology. EFL has received research funding from Celgene, Amgen, Janssen Pharmaceuticals, Monojul, and Kyn Therapeutics. AB is employed by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

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Best, S., Lam, V., Liu, T. et al. Immunomodulatory effects of pevonedistat, a NEDD8-activating enzyme inhibitor, in chronic lymphocytic leukemia-derived T cells. Leukemia 35, 156–168 (2021). https://doi.org/10.1038/s41375-020-0794-0

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