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Title: How the therapeutic cancer drug lenalidomide impacts Natural Killer cell immune responses
Author: Lagrue, Kathryn
ISNI:       0000 0004 5367 5917
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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As multiple myeloma (MM) progresses, Natural Killer (NK) cell responses decline against malignant plasma cells. The immunomodulatory drug lenalidomide is widely used for the treatment of MM but its influence on NK cell biology is unclear. Here, a combination of functional assays and microscopy techniques were used to investigate how lenalidomide affects NK cell activation and effector function. First, lenalidomide lowered the threshold for NK cell activation, causing a 66% decrease in the EC50 for activation through CD16, and a 38% decrease in the EC50 for NKG2D-mediated activation, allowing NK cells to respond to lower doses of ligand. In addition, lenalidomide augmented NK cell responses, causing a 2-fold increase in the proportion of primary NK cells producing IFN-γ, and a 20-fold increase in the amount of IFN-γ produced per cell. Importantly, lenalidomide did not trigger IFN-γ production in unstimulated NK cells. Thus, lenalidomide enhances the NK cell arm of the immune response, without activating NK cells inappropriately. Of particular clinical importance, lenalidomide also allowed NK cells to be activated by lower doses of rituximab, an anti-CD20 mAb widely used to treat B cell malignancies. This supports the combined use of lenalidomide and rituximab in a clinical setting. Second, super resolution STED microscopy revealed that lenalidomide increased the periodicity of cortical actin at immune synapses, resulting in an increase in the area of the actin mesh predicted to be penetrable to vesicles containing IFN-γ. Finally, lenalidomide augmented IFN-γ production and enhanced cortical actin rearrangements in NK cells from MM patients. Interestingly, NK cells from relapsing MM patients showed defective F-actin remodelling compared to NK cells from MM patients in remission. This could be rescued with lenalidomide treatment. This establishes that nanometre-scale rearrangements in cortical actin, a recently discovered step in immune synapse assembly, are a potential new target for therapeutic compounds.
Supervisor: Davis, Daniel ; Selkirk, Murray Sponsor: Biotechnology and Biological Sciences Research Council ; Celgene Corporation (Firm)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available