Immune therapy in multiple myeloma: Can iNKT cells be targeted?

  • Mérédis Favreau ((PhD) Student)
  • Eline Menu (Promotor)
  • Karin Vanderkerken (Promotor)
  • Dirk Elewaut (Promotor)
  • Karine Breckpot (Jury)
  • Koen Venken (Promotor)
  • Moriya Tsuji (Jury)
  • Eva Lion (Jury)
  • Bart Lambrecht (Jury)
  • Brenda De Keersmaecker (Jury)

Student thesis: Doctoral Thesis

Abstract

In the plasma cell cancer multiple myeloma (MM) the invariant natural killer
T cell (iNKT), an unconventional lipid antigen reactive T cell bearing an
important role in anti-tumor immunity, is functionally and numerically
impaired. Therefore, we aimed to unravel and overcome mechanisms
causing iNKT deficiency in MM. We were the first to reveal the leptin – leptin
receptor (LR) axis as an important iNKT-mediating pathway in MM and antitumor
immunity. Increased leptin serum and LR expression levels on iNKTs
were seen during MM progression and leptin was shown to profoundly inhibit
iNKT functionality. iNKT anergy was strongly alleviated by blocking LR
signaling and an almost complete tumor protection in the 5T33MM model
was observed when iNKTs were stimulated in presence of a LR antagonist.
Finally, we provided for the first time an intravital detailed time course of the
iNKT dynamics in response to α-GalCer. Secondly, the implication of
checkpoint molecule PD-1 in mediating iNKT deficiency and deficiencies in
mucosal-associated invariant T cells (MAITs), another invariant T cell subset,
was evaluated. Also MAITs proved to be numerically and functionally
impaired in MM, a novel observation that hasn’t been reported before. This
deficiency was correlated with reduced iNKT numbers in MM patients.
Moreover, MAITs showed poor activation by α-GalCer-stimulated iNKTs,
illustrating a dysfunctional interaction between both. Remarkably, elevated
PD-1 levels were found on both iNKTs and MAITs. A combination of PD-1
blockade and iNKT stimulation was able to significantly rescue iNKT and
MAIT functionality and conferred superior tumor protection in the 5T33MM
model. To conclude, we uncovered new very promising ways to restore the
anti-tumor function of iNKTs in MM.
Date of Award4 Oct 2017
Original languageEnglish
Awarding Institution
  • Vrije Universiteit Brussel
  • Ghent University
SupervisorEline Menu (Promotor), Karin Vanderkerken (Promotor), Koen Venken (Promotor), Dirk Elewaut (Promotor), Karine Breckpot (Jury), Moriya Tsuji (Jury), Eva Lion (Jury), Bart Lambrecht (Jury) & Brenda De Keersmaecker (Jury)

Keywords

  • multiple myeloma
  • plasma cell cancer
  • iNKT
  • anti-tumor immunity

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