Abstract

Introduction: Mantle cell lymphoma (MCL) has had one of the poorest prognoses of all NHL subtypes, and is characterized by a relatively short duration of response, progression-free survival, and time-to-progression, with most patients relapsing. The immunomodulatory drug lenalidomide has shown promising activity in MCL and currently is being investigated further in the clinic for treatment of this tumor. In previous experiments, lenalidomide stimulated proliferation as well as activation of γδ T cells in vitro. Potential mechanisms of lenalidomide’s anti-tumor activity in MCL were investigated here.

Methods: As γδ T lymphocytes mediate anti-tumor effects through antigen recognition and intracellular signaling, we assessed the effect of lenalidomide on tumor cell expression of co-stimulatory and antigen-presenting molecules, as well as other immune response molecules, using microarray analysis. We then assessed the impact of these tumor cell changes on tumor-cell recognition by γδ T lymphocytes. We treated peripheral blood mononuclear cells (PBMCs) from healthy donors with vehicle or lenalidomide. We next purified γδ T cells from control or lenalidomide treated PBMCs and co-cultured them with MCL cells.

Results: Lenalidomide upregulated the expression of several genes involved in the immune response, cell adhesion, cytokine-cytokine receptor interaction, cell cycle and apoptosis by at least 2-fold. In the immune response category, co-stimulatory and antigen-presenting molecules were strongly up regulated including CD86, CD40, CD58, and CD1c. The lenalidomide-induced up-regulation of CD1c was confirmed in MCL lines by quantitative RT-PCR as well as flow cytometry and was also observed in primary B-CLL cells and normal B cells treated with lenalidomide ex-vivo. CD1c, a member of the CD1 family of MHC-like molecules, is expressed mainly in professional antigen-presenting cells, such as B cells, and mediates the presentation of lipid antigens to γδ T cells. Lenalidomide strongly promoted expansion of the Vδ1 subpopulation of γδ T cells and enhanced production of interferon-g. Treatment of MCL cells and γδ T cells with lenalidomide induced changes in the organization of the actin cytoskeleton, re-localization of surface markers and enhanced the number of γδ T-MCL synapses. Furthermore, gd T cells, expanded in the presence of lenalidomide, had enhanced killing activity against MCL cells.

Conclusion: Our studies show that lenalidomide might provide dual activity against MCL cells by inducing expression of CD1c in the tumor cells and by enhancing γδ T cell-mediated cytotoxicity. The therapeutic implications, as well as the prospects for novel biomarker development will be discussed further.

Disclosures: Gaidarova:Celgene: Employment, Equity Ownership. Corral:Celgene: Employment, Equity Ownership. Gleizer:Celgene: Employment, Equity Ownership. Young:Celgene: Employment, Equity Ownership. Brady:Celgene: Employment, Equity Ownership. Bennett:Celgene: Employment, Equity Ownership. Lopez-Girona:Celgene: Employment, Equity Ownership.

Author notes

Corresponding author