Activation of NK cells and disruption of PD-L1/PD-1 axis: two different ways for lenalidomide to block myeloma progression

Massimo Giuliani, Bassam Janji _ and Guy Berchem

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Oncotarget. 2017; 8:24031-24044. https://doi.org/10.18632/oncotarget.15234

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Massimo Giuliani1, Bassam Janji1,* and Guy Berchem1,2,*

1 Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg

2 Department of Hemato-Oncology, Centre Hospitalier du Luxembourg, Luxembourg City, Luxembourg

* These authors have equally contributed to this work

Correspondence to:

Bassam Janji, email:

Keywords: lenalidomide, multiple myeloma, NK cells, PD-L1/PD-1, immunotherapy

Received: July 07, 2016 Accepted: January 16, 2017 Published: February 09, 2017


Natural Killer (NK) cells play a critical role against tumor cells in hematological malignancies. Their activating receptors are essential in tumor cell killing. In Multiple Myeloma (MM) patients, NK cell differentiation, activation and cytotoxic potential are strongly impaired leading to MM escape from immune surveillance in tissues and bone marrow. Mechanisms used by MM to affect NK cell functions are mediated by the release of soluble factors, the expression of activating and inhibitory NK cell ligands, and the expression of immune check-point inhibitors. Lenalidomide represents an efficient clinical approach in MM treatment to improve patients’ survival. Lenalidomide does not only promotes tumor apoptosis, but also stimulates T and NK cells, thereby facilitating NK-mediated tumor recognition and killing. This occurs since Lenalidomide acts on several critical points: stimulates T cell proliferation and cytokine secretion; decreases the expression of the immune check-point inhibitor Programmed Death-1 (PD-1) on both T and NK cells in MM patients; decreases the expression of both PD-1 and PD-L1 on MM cells; promotes MM cell death and abrogates MM/stromal microenvironment cross-talk, a process known to promote the MM cell survival and proliferation. This leads to the inhibition of the negative signal induced by PD-1/PD-L1 axis on NK cells, restoring NK cell cytotoxic functions. Given the importance of an effective immune response to counteract the MM progression and the promising approaches using anti-PD-1/PD-L1 strategies, we will discuss in this review how Lenalidomide could represent an adequate approach to re-establish the recognition against MM by exhausted NK cell.

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