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MULTIPLE MYELOMA, GAMMOPATHIES

Targeting ubiquitin-specific protease-7 in plasmacytoid dendritic cells triggers anti-myeloma immunity

Leukemia volume 35, pages 2435–2438 (2021)Cite this article

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Proteasome inhibitors (PIs) are a backbone standard of care in the treatment of relapsed/refractory and newly diagnosed multiple myeloma (MM) [1, 2]. Although PIs represent a major advance, not all MM responds, and relapse develops due to the development of drug-resistance [2]. The mechanism(s) that contribute to PI-resistance include mutations in PI-binding site in the β-5 chymotrypsin-like proteasome subunit [3, 4]; increased transcription and synthesis/activity of proteasome catalytic subunits [4]; insufficient blockade of proteasomal activity by PI [5]; induction of XBP1 and heat shock proteins [5]; repression of 19S subunits via DNA methylation [6]; and upregulation of alternative protein degradation pathway (e.g., aggresome/autophagy). In addition to the 26S proteasome, the ubiquitin-proteasome pathway harbors many other potential sites for pharmacological intervention, with the potential to overcome PI-resistance. In this context, our prior studies showed that genetic and biochemical inhibition of deubiquitylating enzyme USP7, upstream of 20S proteasome, can trigger apoptosis in MM cells resistant to PI therapies via p53/p21 signaling axis, without affecting proteasomal activity [7].

Besides tumor-intrinsic mechanism(s), the interaction of MM cells with BM accessory cells and immune effector cells also stimulates tumor growth, drug-resistance, and immune suppression. For example, cell–cell contact between immunologically-defective plasmacytoid dendritic cells (pDCs) with MM cells, T- or NK-effector cells in the BM milieu induces MM cell proliferation, as well as inhibits innate and adaptive immune responses. Using our co-culture models of patient pDCs, T cells, or NK cells with autologous MM cells [8, 9], we have identified mechanisms of immune suppression and validated novel targeted therapies to restore anti-MM immunity. For example, triggering maturation/activation of MM patient pDCs via TLR7/9 agonist or anti-PD-L1 Abs in these models restores their ability to stimulate T-cell proliferation and cytolytic activity against MM cells [8,9,10]. Our prior study showed that targeting USP7 DUB in MM cells overcomes PI-resistance [7]. In the current study, we utilized our co-culture models of pDCs, T cells, or NK cells with autologous patient MM cells to examine whether USP7 inhibition also stimulates anti-MM immunity.

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Fig. 1: Pharmacological inhibition of USP7 activates MM patient pDCs and triggers pDC-induced MM-specific CD8+ CTLs.
Fig. 2: USP7 blockade triggers NK cell-mediated MM cell lysis and decreases T regulatory cells in MM patient BM.

References

  1. Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist. 2003;8:508–13. https://doi.org/10.1634/theoncologist.8-6-508. PMID: 14657528

    Article  PubMed  Google Scholar 

  2. Anderson KC. Therapeutic advances in relapsed or refractory multiple myeloma. J Natl Compr Canc Netw. 2013;11:676–9.

    Article  CAS  Google Scholar 

  3. Franke NE, Niewerth D, Assaraf YG, van Meerloo J, Vojtekova K, van Zantwijk CH, et al. Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia. 2012;26(Apr):757–68. https://doi.org/10.1038/leu.2011.256. Epub 2011 Sep 23PMID: 21941364.

    Article  CAS  PubMed  Google Scholar 

  4. Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJ, Cloos J. Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Update. 2015;18:18–35. https://doi.org/10.1016/j.drup.2014.12.001. PMID: 25670156

    Article  Google Scholar 

  5. Lü S, Wang J. The resistance mechanisms of proteasome inhibitor bortezomib. Biomark Res. 2013;1(Mar):13 https://doi.org/10.1186/2050-7771-1-13. PMID: 24252210; PMCID: PMC4177604.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tsvetkov P, Sokol E, Jin D, Brune Z, Thiru P, Ghandi M, et al. Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers. Proc Natl Acad Sci USA. 2017;114(Jan):382–7. https://doi.org/10.1073/pnas.1619067114. Epub 2016 Dec 27PMID: 28028240; PMCID: PMC5240730.

    Article  CAS  PubMed  Google Scholar 

  7. Chauhan D, Tian Z, Nicholson B, Kumar KG, Zhou B, Carrasco R, et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell. 2012;22:345–58. PMID: 22975377; PMCID: PMC3478134

    Article  CAS  Google Scholar 

  8. Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell. 2009;16(Oct):309–23. https://doi.org/10.1016/j.ccr.2009.08.019. PMID: 19800576; PMCID: PMC2762396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ray A, Das DS, Song Y, Richardson P, Munshi NC, Chauhan D, et al. Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia. 2015;29(Jun):1441–4. https://doi.org/10.1038/leu.2015.11. Epub 2015 Jan 30. PMID: 25634684; PMCID: PMC5703039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ray A, Tian Z, Das DS, Coffman RL, Richardson P, Chauhan D. et al. A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib. Leukemia. 2014;28(Aug):1716–24. https://doi.org/10.1038/leu.2014.46. Epub 2014 Jan 30. PMID: 24476765; PMCID: PMC4116471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schauer NJ, Liu X, Magin RS, Doherty LM, Chan WC, Ficarro SB, et al. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Sci Rep. 2020;10(Mar):5324 https://doi.org/10.1038/s41598-020-62076-x. PMID: 32210275; PMCID: PMC7093416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pittari G, Vago L, Festuccia M, Bonini C, Mudawi D, Giaccone L, et al. Restoring natural killer cell immunity against multiple myeloma in the era of new drugs. Front Immunol. 2017;8(Nov):1444 https://doi.org/10.3389/fimmu.2017.01444. PMID: 29163516; PMCID: PMC5682004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011;241(May):260–8. https://doi.org/10.1111/j.1600-065X.2011.01018.x. PMID: 21488902; PMCID: PMC3077798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hibino S, Chikuma S, Kondo T, Ito M, Nakatsukasa H, Omata-Mise S, et al. Inhibition of Nr4a receptors enhances antitumor immunity by breaking Treg-mediated immune tolerance. Cancer Res. 2018;78(Jun):3027–40. https://doi.org/10.1158/0008-5472.CAN-17-3102. Epub2018 Mar 20. PMID: 29559474.

    Article  CAS  PubMed  Google Scholar 

  15. Jang JE, Hajdu CH, Liot C, Miller G, Dustin ML, Bar-Sagi D. Crosstalk between regulatory T cells and tumor-associated dendritic cells negates anti-tumor immunity in pancreatic cancer. Cell Rep. 2017;20(Jul):558–71. https://doi.org/10.1016/j.celrep.2017.06.062. PMID: 28723561; PMCID: PMC5649374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The grant support for this investigation was provided by National Institutes of Health Specialized Programs of Research Excellence (SPORE) grant P50100707, R01CA207237, PO1 CA155258, and RO1 CA050947. This work was supported in part by Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Riney Family Multiple Myeloma Initiative. Krishan Chauhan helped with statistical analysis, literature research, and figure artwork. KCA is an American Cancer Society Clinical Research Professor.

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  1. These authors contributed equally: Dharminder Chauhan, Kenneth C. Anderson

Authors and Affiliations

  1. The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Arghya Ray, Ting Du, Yan Song, Dharminder Chauhan & Kenneth C. Anderson

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Sara J. Buhrlage

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  1. Arghya Ray
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Contributions

DC conceptualized the project, designed research, interpreted data, and wrote the manuscript; AR performed all the experiments; analyzed and approved the final data; TD and YS helped with bone marrow sample preparations for assays; SJB provided the inhibitor; and KCA provided clinical samples, as well as reviewed the data and manuscript.

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Correspondence to Dharminder Chauhan or Kenneth C. Anderson.

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Conflict of interest

KCA is on Advisory Boards of Millenium-Takeda, Gilead, Janssen, Sanofi-Aventis, and Bristol Myers Squibb; and is a Scientific Founder of Oncopep and C4 Therapeutics. DC is a consultant to Stemline Therapeutics, Inc., Oncopeptide AB, and an Equity owner in C4 Therapeutics. The remaining authors declare no conflict of interest. Other authors have no competing financial interests.

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Ray, A., Du, T., Song, Y. et al. Targeting ubiquitin-specific protease-7 in plasmacytoid dendritic cells triggers anti-myeloma immunity. Leukemia 35, 2435–2438 (2021). https://doi.org/10.1038/s41375-021-01129-0

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