Preclinical Evaluation of Invariant Natural Killer T Cells in the 5T33 Multiple Myeloma Model

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

doi:10.1371/journal.pone.0065075

Abstract

Immunomodulators have been used in recent years to reactivate host anti-tumor immunity in several hematological malignancies. This report describes the effect of activating natural killer T (NKT) cells by α-Galactosylceramide (α-GalCer) in the 5T33MM model of multiple myeloma (MM). NKT cells are T lymphocytes, co-expressing T and NK receptors, while invariant NKT cells (iNKTs) also express a unique semi-invariant TCR α-chain. We followed iNKT numbers during the development of the disease in both 5T33MM mice and MM patients and found that their numbers dropped dramatically at the end stage of the disease, leading to a loss of total IFN-γ secretion. We furthermore observed that α-GalCer treatment significantly increased the survival of 5T33MM diseased mice. Taken together, our data demonstrate for the first time the possibility of using a preclinical murine MM model to study the effects of α-GalCer and show promising results of α-GalCer treatment in a low tumor burden setting.

Highlights

Natural killer T (NKT) cells are T lymphocytes that act as a functional bridge between the innate and the acquired immunity; they have a crucial effect in tumor and pathogen resistance as well as autoimmunity [1,2,3]
The percentage was significantly decreased in spleen from 1.1%60.48 in naive to 0.6%60.18 in 5T33MM mice, while in bone marrow (BM) we saw a significant upregulation of invariant NKT cells (iNKTs) number from 0.18%60.13 to 0.43%60.16 and no significant differences in the blood
We found a significant drop in liver and spleen iNKT number, while we saw a small but significant upregulation of iNKTs in the BM, indicating that a part of the iNKTs migrated to the tumor

Summary

Introduction

Natural killer T (NKT) cells are T lymphocytes that act as a functional bridge between the innate and the acquired immunity; they have a crucial effect in tumor and pathogen resistance as well as autoimmunity [1,2,3]. Other studies indicated the development of iNKT anergy after a-GalCer injection, possibly due to presentation by non-professional APCs which lack the proper co-stimulatory signals [4,14] To overcome this problem, a-GalCer was loaded onto mature DCs which resulted in a large expansion of iNKTs, leading to a more prolonged response and induced more potent resistance to tumor development [5,14,16]. Dhodapkar et al demonstrated that in progressive MM, iNKTs are still detectable in the blood and tumor microenvironment but they have a profound deficiency in their IFN-c production while in MGUS (monoclonal gammopathy of unknown significance) patients, the deficiency was potentially reversible [16] This defect could be overcome in vitro as described above by using DCs loaded with a-GalCer [14,16].

Methods

Results

Conclusion