Dynamics of natural killer cell homeostasis : implications for cell-based cancer immunotherapy

• Natural killer (NK) cells comprise a central role within the innate immune system, eliminating virally infected, foreign and transformed cells through their natural cytotoxic capacity. Release of their cytotoxic granules is tightly controlled through the balance of a large repertoire of inhibitory and activating receptors, and it is the unique combination of these receptors on individual cells that confers them their immense diversity both in phenotype and functionality. This thesis aimed to investigate the mechanisms sustaining NK cell homeostasis with the aim of translating these findings into more efficient NK cell-based immunotherapies against cancer. In paper I, we set out to define a transcriptional timeline for NK cell differentiation through the use of single-cell RNA sequencing of unique differentiation subsets ranging from CD56bright to adaptive NKG2C+CD56dim NK cells. Transcriptional differentiation was concentrated within the surprisingly diverse CD56bright subset which gradually transitioned into CD56dim NK cells before terminal differentiation into adaptive CD56dim NK cells. The vastly diverse yet unique NK cell repertoire within an individual is surprisingly stable over time considering the constant renewal of these cells at steady state. In paper II, we performed an in-depth analysis of homeostatic proliferation in human NK cells. We identified a high degree of intra-lineage plasticity combined with transcriptional reprogramming associated with the acquired phenotype as the underlying mechanisms maintaining repertoire stability at steady state. In paper III, we examined the role of NK cells in a setting of perturbed homeostasis, namely patients with high-risk myelodysplastic syndrome undergoing immunomodulatory treatment with 5-azacytidine. We identified a role for 5-azacytidine in modifying the global NK cell repertoire, as uptake of the drug by proliferating NK cells resulted in increased expression of killer cell immunoglobulin-like receptors (KIR) and improved functionality. In paper IV we identified a dose-dependent cytokine addiction in IL-15 expanded NK cells, leading to the induction of apoptosis upon cytokine withdrawal. A proliferation-dependent induction of the short splice variant of BIM, combined with an altered BCL-2/BIM ratio resulted in sensitization to cell death post withdrawal. This thesis provides new insights into the dynamic nature of NK cell homeostasis, from understanding NK cell differentiation at the transcriptional level to perturbations after cytokine stimulation and immunomodulatory therapies.

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