Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities.

Aude Le Roy,Samuel Granjeaud,Florence Riccardi,Florence Orlanducci,Daniel Olive,Jean-Louis Mege,Rémy Castellano,Amira Ben Amara,Yves Collette,Thomas Prébet,Armelle Goubard,Audrey Benyamine,Norbert Vey,Jean-Jacques Fournié,Céline Castanier,Cyril Fauriat,Frédéric Pont

doi:10.3389/fimmu.2018.00977

Abstract

Immunomodulatory drugs (IMiDs) are anticancer drugs with immunomodulatory, anti-angiogenesis, anti-proliferative, and pro-apoptotic properties. IMiDs are currently used for the treatment of multiple myeloma, myelodysplastic syndrome, and B-cell lymphoma; however, little is known about efficacy in acute myeloid leukemia (AML). We proposed in this study to investigate the relevance of IMiDs therapy for AML treatment. We evaluated the effect of IMiDs on primary AML blasts (n = 24), and the impact in natural killer (NK) cell-mediated immunosurveillance of AML. Using primary AML cells and an immunodeficient mouse leukemia xenograft model, we showed that IMiDs induce AML cell death in vitro and impair leukemia progression in vivo. In addition, treatment of AML blasts with IMiDs resulted in enhanced allogeneic NK cell anti-leukemia reactivity. Treatment by pomalidomide of AML blasts enhanced lysis, degranulation, and cytokine production by primary allogeneic NK cells. Furthermore, the treatment with lenalidomide of patients with myeloid malignancies resulted in NK cell phenotypic changes similar to those observed in vitro. IMiDs increased CD56 and decreased NKp30, NKp46, and KIR2D expression on NK cells. Finally, AML blasts treatment with IMiDs induced phenotypic alterations including downregulation of HLA-class I. The effect of pomalidomide was not correlated with cereblon expression and A/G polymorphism in AML cells. Our data revealed, a yet unobserved, dual effects on AML affecting both AML survival and their sensitivity to NK immunotherapy using IMiDs. Our study encourages continuing investigation for the use of IMiDs in AML, especially in combination with conventional therapy or immunotherapy strategies.

Highlights

Thalidomide derivatives lenalidomide and pomalidomide are a class of oral anticancer agents known as immunomodulatory drugs (IMiDs)
To evaluate the cytotoxic effect of pomalidomide in acute myeloid leukemia (AML), primary AML cells from 23 patients at diagnosis were cultured with pomalidomide for 48 h, harvested, and subjected to viability analysis by flow cytometry
We further assessed antitumor efficacy of pomalidomide in vivo using NSG mice xenografted with human primary AML blasts

Summary

Introduction

Thalidomide derivatives lenalidomide and pomalidomide are a class of oral anticancer agents known as immunomodulatory drugs (IMiDs). They are currently used in a variety of hematologic malignancies. IMiDs directly exert antitumor activity through different therapeutically relevant effects such as angiogenesis inhibition [5, 6], inhibition of cancer cell proliferation [7,8,9], and induction of apoptosis [10]. Many studies suggest that increased IL-2 production induced by IMiDs leads to natural killer (NK) cell activation, proliferation, and NK cell-mediated ADCC against tumor cells [6, 12, 15,16,17,18]. Direct effects of lenalidomide have been described by modification of NK cell phenotype without consequence on the cytotoxic potential of NK cells [19]

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