Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Multiple Myeloma, Gammopathies

Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma

Leukemia volume 31, pages 2678–2685 (2017)Cite this article

Subjects

Abstract

A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Rajkumar SV, Kumar S . Multiple myeloma: diagnosis and treatment. Mayo Clin Proc 2016; 91: 101–119.

    Article  PubMed  Google Scholar 

  2. Lemaire M, Deleu S, De Bruyne E, Van Valckenborgh E, Menu E, Vanderkerken K . The Microenvironment and molecular biology of the multiple myeloma tumor. Adv Cancer Res 2011; 110: 19–42.

    Article  CAS  PubMed  Google Scholar 

  3. Caers J, Deleu S, Belaid Z, De Raeve H, Van Valckenborgh E, De Bruyne E et al. Neighboring adipocytes participate in the bone marrow microenvironment of multiple myeloma cells. Leukemia 2007; 21: 1580–1584.

    Article  CAS  PubMed  Google Scholar 

  4. Naveiras O, Nardi V, Wenzel PL, Fahey F, Daley GQ . Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment. Nature 2009; 460: 259–263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mathis D, Shoelson S . Immunometabolism: an emerging frontier. Nat Rev Immunol 2011; 11: 81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schipper HS, Rakhshandehroo M, Van De Graff SFJ, Venken K, Koppen A, Stienstra R et al. Natural killer T cells in adipose tissue prevent insulin resistance. J Clin Invest 2012; 122: 3343–3354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Huh JY, Kim I, Park J, Hwang J, Lee S, Sohn H et al. A novel function of adipocytes in lipid antigen presentation to iNKT Cells. Mol Cell Biol 2013; 33: 328–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Favreau M, Vanderkerken K, Elewaut D, Venken K, Menu E . Does an NKT-cell-based immunotherapeutic approach have a future in multiple myeloma ? Oncotarget 2016; 7: 23128–23140.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Dhodapkar MV, Geller MD, Chang DH, Shimizu K, Fujii S-I, Dhodapkar KM et al. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med 2003; 197: 1667–1676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nur H, Fostier K, Aspeslagh S, Renmans W, Bertrand E, Leleu X . Preclinical evaluation of invariant natural killer T cells in the 5T33 multiple myeloma model. PLoS One 2013; 8: e65075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chan a C, Neeson P, Leeansyah E, Tainton K, Quach H, Prince HM et al. Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy. Clin Exp Immunol 2014; 175: 49–58.

    Article  PubMed  Google Scholar 

  12. Dhodapkar MV, Richter J . Harnessing natural killer T (NKT) cells in human myeloma: Progress and challenges. Clin Immunol 2011; 140: 160–166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Spanoudakis E, Hu M, Naresh K, Terpos E, Melo V, Reid A et al. Regulation of multiple myeloma survival and progression by CD1d. Blood 2009; 113: 2498–2507.

    Article  CAS  PubMed  Google Scholar 

  14. Vanderkerken K, Croucher P . Multiple myeloma biology: lessons from the 5TMM models. Immunol Rev 2003; 194: 196–206.

    Article  CAS  PubMed  Google Scholar 

  15. Lutz MB, Kukutsch N, Ogilvie ALJ, Roßner S, Koch F, Romani N et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 1999; 223: 77–92.

    Article  CAS  PubMed  Google Scholar 

  16. Jacques P, Venken K, Beneden K, Van, Hammad H, Seeuws S, Drennan MB et al. Invariant natural killer T cells are natural regulators of murine spondylarthritis. Arthritis Rheum 2010; 62: 988–999.

    Article  CAS  PubMed  Google Scholar 

  17. Govindarajan S, Elewaut D, Drennan M . An optimized method for isolating and expanding invariant natural killer T cells from mouse spleen. J Vis Exp 2015; 105: e53256.

    Google Scholar 

  18. Zabeau L, Verhee A, Catteeuw D, Faes L, Seeuws S, Decruy T et al. Selection of non-competitive leptin antagonists using a random nanobody-based approach. Biochem J 2011; 441: 425–434.

    Article  Google Scholar 

  19. Radl J, De Glopper E, Schuit HRE, Zucher C . Idiopathic paraproteinemia: II. transplantation of the paraprotein-producing clone from old to young C57BL/KaLwRij mice. J Immunol 1979; 122: 609–613.

    CAS  PubMed  Google Scholar 

  20. Venken K, Seeuws S, Zabbeau L, Jacques P, Decruy T et al. A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis. J Hepatol 2014; 60: 175–182.

    Article  CAS  PubMed  Google Scholar 

  21. Vanderkerken K, De Raeve H, Goes E, Van Meirvenne S, Radl J, Van Riet I et al. Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL/KaLwRij mouse. Br J Cancer 1997; 76: 451–460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Radl J, De Glopper E, Schuit HR, Zurcher C . Idiopathic paraproteinemia. II. Transplantation of the paraprotein-producing clone from old to young C57BL/KaLwRij mice. J Immunol 1979; 122: 609–613.

    CAS  PubMed  Google Scholar 

  23. Singh AK, Gaur P, Das SN . Natural killer T cell anergy, co-stimulatory molecules and immunotherapeutic interventions. Hum Immunol 2014; 75: 250–260.

    Article  CAS  PubMed  Google Scholar 

  24. Iyoda T, Ushida M, Kimura Y, Minamino K, Hayuka A, Yokohata S et al. Invariant NKT cell anergy is induced by a strong TCR-mediated signal plus co-stimulation. Int Immunol 2010; 22: 905–913.

    Article  CAS  PubMed  Google Scholar 

  25. Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H et al. PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. J Immunol 2009; 182: 2816–2826.

    Article  CAS  PubMed  Google Scholar 

  26. Velázquez P, Cameron TO, Kinjo Y, Nagarajan N, Kronenberg M, Dustin ML . Cutting edge: activation by innate cytokines or microbial antigens can cause arrest of natural killer T cell patrolling of liver sinusoids. J Immunol 2016; 180: 2024–2028.

    Article  Google Scholar 

  27. Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol 2005; 3: e113.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Mattarollo SR, West AC, Steegh K, Duret H, Paget C, Martin B et al. NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma. Blood 2012; 120: 3019–3029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lynch L, Shea DO, Winter DC, Geoghegan J, Doherty GD, O'Farrelly C . Invariant NKT cells and CD1d+cells amass in human omentum and are depleted in patients with cancer and obesity. Eur J Immunol 2009; 39: 1893–1901.

    Article  CAS  PubMed  Google Scholar 

  30. Ji Y, Sun S, Xu A, Bhargava P, Yang L, Lam KSL et al. Activation of natural killer T cells promotes M2 macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J Biol Chem 2012; 287: 13561–13571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lynch L . Adipose invariant natural killer T cells. Immunology 2014; 142: 337–346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Merico F, Bergui L, Gregoretti MG, Ghia P, Aimo G, Lindley IJ et al. Cytokines involved in the progression of multiple myeloma. Clin Exp Immunol 1993; 92: 27–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Atanackovic D, Hildebrandt Y, Templin J, Cao Y, Keller C, Panse J et al. Role of interleukin 16 in multiple myeloma. J Natl Cancer Inst 2012; 104: 1005–1020.

    Article  CAS  PubMed  Google Scholar 

  34. Lee C, Oh J, Park J, Choi J, Bae E, Lee H et al. TNF α mediated IL-6 secretion is regulated by JAK/STAT pathway but not by MEK phosphorylation and AKT phosphorylation in U266 multiple myeloma cells. Biomed Res Int 2013; 12: 580135.

    Google Scholar 

  35. Parekh VV, Wilson MT, Olivares-villagómez D, Singh AK, Wu L, Wang C et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest 2005; 115: 2572–2583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rush CM, Millington OR, Hutchison S, Bryson K, Brewer JM, Garside P . Characterization of CD4+ T-cell-dendritic cell interactions during secondary antigen exposure in tolerance and priming. Immunology 2009; 128: 463–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mullen M, Gonzalez-Perez R . Leptin-induced JAK/STAT signaling and cancer growth. Vaccines 2016; 4: E26.

    Article  PubMed  Google Scholar 

  38. Procaccini C, De Rosa V, Galgani M, Carbone F, Cassano S, Greco D et al. Leptin-induced mTOR activation defines a specific molecular and transcriptional signature controlling CD4+ effector T cell responses. J Immunol 2012; 189: 2941–2953.

    Article  CAS  PubMed  Google Scholar 

  39. El-Masry O, Al-Sakkaf K, Brown B, Dobson P . Differential crosstalk between the AMPK and PI3K/Akt pathways in breast cancer cells of differing genotypes: leptin inhibits the effectiveness of AMPK activation. Oncol Rep 2015; 34: 1675–1680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wauman J, Tavernier J . Leptin receptor signaling: pathways to leptin resistance. Front Biosci 2011; 16: 2771–2793.

    Article  CAS  Google Scholar 

  41. Wu J, Shin J, Xie D, Wang H, Gao J, Zhong X-P . Tuberous sclerosis 1 promotes invariant NKT cell anergy and inhibits invariant NKT cell-mediated antitumor immunity. J Immunol 2014; 192: 2643–2650.

    Article  CAS  PubMed  Google Scholar 

  42. Ramakrishnan V, D’Souza A . Signaling pathways and emerging therapies in multiple myeloma. Curr Hematol Malig Rep 2016; 11: 156–164.

    Article  PubMed  Google Scholar 

  43. Ikeda S, Okamoto T, Okano S, Umemoto Y, Tagawa T, Morodomi Y et al. PD-L1 Is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. J Thorac Oncol 2016; 11: 62–71.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Carine Seynaeve, Sofie Seghers, Tine Decruy, Nadia Schryvers and Nathalie Jouy for expert technical assistance and SVC for generating the glycolipid antigens. MF is a doctoral fellow supported by KotK, EM is post-doctoral fellow supported by AXA Research Foundation. DG is post-doctoral fellow supported by Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO-Vl) and Stichting Tegen Kanker. K Venken is post-doctoral fellow of FWO-Vl. JT is recipient of European Research Council (ERC) Advanced Grant. SF is supported by FWO-Vl. DE is supported by FWO-Vl, Stichting Tegen Kanker, Research Council of Ghent University and interuniversity Attraction Pole grant Devrepair from Belspo Agency (project P7/07). This project received funding from Kom op Tegen Kanker, Stichting Tegen Kanker FWO-Vl and EU’s seventh framework program under EC-GA no. 305266 ‘MIAMI’.

Author information

Author notes

  1. M Favreau, E Menu, D Gaublomme, K Venken and D Elewaut: These authors contributed equally to this work.

  2. Shared supervision.

Authors and Affiliations

  1. Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium

    M Favreau, E Menu, K Vanderkerken, S Faict, K Maes & E De Bruyne

  2. Department of Rheumatology, Ghent University Hospital, Ghent, Belgium

    M Favreau, D Gaublomme, S Govindarajan, M Drennan, K Venken & D Elewaut

  3. Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent University, Ghent, Belgium

    M Favreau, D Gaublomme, S Govindarajan, M Drennan, K Venken & D Elewaut

  4. Department of Pharmaceutics, Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium

    S Van Calenbergh

  5. Service d’Hématologie et Thérapie Cellulaire, Pôle Régional de Cancérologie, Hospital de la Miléterie, Poitiers, France

    X Leleu

  6. Department of Biochemistry, VIB Medical Biotechnology Center, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    L Zabeau & J Tavernier

Authors
  1. M Favreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Menu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Gaublomme
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Vanderkerken
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Faict
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Maes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E De Bruyne
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Govindarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Drennan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Van Calenbergh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. X Leleu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. L Zabeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Tavernier
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K Venken
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. D Elewaut
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Elewaut.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Favreau, M., Menu, E., Gaublomme, D. et al. Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma. Leukemia 31, 2678–2685 (2017). https://doi.org/10.1038/leu.2017.146

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2017.146

This article is cited by

Search

Advanced search

Quick links