prof. Dirk Elewaut (MD, PhD)
principal investigator - Laboratory of Molecular Immunology and Inflammation - UZ Gent/VIB-UGent
(head) clinician - Rheumatology - UZ Gent
full professor - Faculty of Medicine and Health Sciences - UGent
Invariant Natural Killer T (iNKT) cells recognize glycolipids such as α-galactosylceramide (α-GalCer) and have the ability to rapidly produce large amounts of immunodulatory cytokines upon stimulation. Importantly, iNKT cell activation is considered a promising approach in cancer treatment. In addition to cytokine-mediated anti-tumor action, such as the activation of other cytotoxic lymphocytes through IFN-γ production, iNKT cells can exert direct cytotoxicity against tumor cells. Clinical applicability of glycolipid analogues such as α-GalCer is limited because they induce iNKT cell hyporesponsiveness and a 'mixed' cytokine species with potentially conflicting functionality in tumor rejection. We developed novel α-GalCer analogues with a marked Th1 bias (i.e. leading to preferential IFN-γ production) in both mice and men, leading to superior protection against the establishment of long tumor nodules in vivo.
We were also able to demonstrate the importance of iNKT cell activity in multiple myeloma (MM). MM is a B-cell malignancy hallmarked by uncontrolled accumulation of plasma cells in the bone marrow (BM) which remains mostly incurable. We were able to show a significantly decreased number of iNKT cells in the blood of MM patients. Moreover, these cells were found to be functionally impaired, showing a greatly reduced potential to produce IFN-γ. Despite the functional impairment, treatment of 5T33MM mice with α-GalCer-pulsed DCs still managed to prolong survival times.
Human MM patients were shown to have elevated leptin serum levels. Moreover, leptin receptor expression was strongly increased on iNKT cells. We demonstrated that leptin receptor blocking could significantly improve the anti-tumoral effect of α-GalCer stimulation by overcoming iNKT cell hyporesponsiveness, revealing the potential for a novel method for checkpoint inhibition in iNKT cell immunotherapy.
- prof. Dirk Elewaut (MD, PhD) - principal investigator, clinician, full professor
- dr. Koen Venken (PhD) - post-doctoral fellow
- dr. Djoere Gaublomme (PhD) - post-doctoral fellow
- dr. Srinath Govindarajan (PhD) - post-doctoral fellow
- dr. Anton De Spiegeleer (MD) - doctoral fellow
- Tine Decruy - technician
- Eveline Verheugen - technician
- Nadia Schryvers - technician
- Julie Coudenys - technician
- Sarah Trypsteen - animal caretaker
- 'Checkpoint inhibition in the treatment of multiple myeloma: A way to boost innate-like T cell anti-tumor function?'. Molecular Immunology, 2018. (PMID: 30153633)
- 'Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma'. Leukemia, 2017. (PMID: 28490813)
- 'Both mucosal-associated invariant and natural killer T-cell deficiency in multiple myeloma can be countered by PD-1 inhibition'. Haematologica, 2017. (PMID: 28385777)
- 'The role of Ly49E receptor expression on murine intraepithelial lymphocytes in intestinal cancer development and progression'. Cancer immunology, immunotherapy, 2016. (PMID: 27585789)
- 'Does an NKT-cell-based immunotherapeutic approach have a future in multiple myeloma?'. Oncotarget, 2016. (PMID: 26895468)
- 'Enhanced TCR footprint by a novel glycolipid increases NKT-dependent tumor protection.' Journal of immunology, 2013. (PMID: 23960235)
- 'Preclinical evaluation of invariant natural killer T cells in the 5T33 multiple myeloma model'. PLoS One, 2013. (PMID: 23741460)
- ' Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis'. The EMBO journal, 2011. (PMID: 21552205)
Contact & links
- Lab address: Campus UZ Gent, MRB2, Corneel Heymanslaan 10, 9000 Gent
- FOCIS (Federation of Clinical Immunology Societies) is a center of excellence that exists to improve human health through immunology by fostering interdisciplinary approaches to both understand and treat immune-based diseases.
- EULAR (European League Against Rheumatism) is a center of excellence that aims to to reduce the burden of rheumatic diseases on the individual and society and to improve the treatment, prevention and rehabilitation of musculoskeletal diseases.