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Multiple Myeloma, Gammopathies

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

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.

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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’.

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Correspondence to D Elewaut.

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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

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