Invariant Natural Killer T cells in the 5T33 multiple myeloma model

Haneen Nur, Karel Fostier, Sandrine Aspeslagh, Wim Renmans, Elisabeth Bertrand, Xavier Leleu, Karine Breckpot, Henri Schots, Marc De Waele, Els Van Valckenborgh, Elke De Bruyne, Thierry Facon, Dirk Elewaut, Karin Vanderkerken, Eline Menu

Research output: Contribution to journalConference paper

19 Citations (Scopus)

Abstract

Invariant Natural Killer T cells (iNKTs) are T-lymphocytes co-expressing T and NK receptors. It has been described that iNKTs have an anti-tumor activity through the activation of their unique TCR alpha-chain by alpha-Galactosylceramide (a-GalCer) in the context of CD1d molecules. Therefore, stimulating iNKTs in the 5T33 multiple myeloma model can be a useful preclinical tool.

We followed the frequency of iNKTs during the development of the disease in both 5T33MM mice and MM patients and found that their numbers declined dramatically at the end stage of the disease (from 7% to 2.6% in mice liver cells and from 737 to 76 iNKT/ml in blood of relapsed patients). We analysed the activity of these iNKTs through IFNalpha secretion by co-culturing liver iNKTs with a-GalCer loaded DCs. We found that IFNalpha dropped from 2.3 ng/ml to undetectable levels at end stage of the disease which is the result of the decline in iNKT number and not through internalization of their Valpha14 receptors as determined by RT-PCR.

We investigated the response of iNKTs to a-GalCer in vivo and found that the IFNalpha response in non-terminal diseased mice was equal to that measured in naive mice, confirming the possibility of inducing Th1 responses with a-GalCer. We furthermore found that a-GalCer treatment significantly increased the survival of 5T33MM mice from 22 to 29 days.

To examine whether a-GalCer activation of iNKTs has an effect on tumor angiogenesis, 5T33MM mice were treated with a-GalCer at 4 day intervals. A significant decrease of the microvessel density (MVD) was observed in the treated group (23.7%) compared to untreated group (33.3%), almost back to naive levels (19%). This was independent of the reduction in tumor load. Rat aortic ring assays were performed to confirm that IFNalpha mediates the inhibition of angiogenesis.

These data demonstrate for the first time the possibility of using a preclinical MM model to study the effects of a-GalCer on iNKTs and shows promising results of treating early-stage MM patients.
Original languageEnglish
Pages (from-to)26-26
Number of pages1
JournalBelgian Journal of Hematology
Issue number2013
Publication statusPublished - 24 Jan 2013

Keywords

  • myeloma

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