Arellano Ballestero, Helena; (2024) Defining the critical characteristics of Natural Killer cell memory. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Natural killer (NK) cells are cytotoxic lymphocytes capable of rapidly eliminating viral- and tumour-transformed cells. Fascinating earlier evidence suggests an intrinsic capacity of natural killer (NK) cells to acquire features of immunological memory in the context of cytomegalovirus (CMV) infection or pro-inflammatory cytokine stimulation (CIML-NK). We and others have identified that priming NK cells with specific cancer cell lines induces tumour-primed NK (TpNK) cells, which are capable of lysing previous resistant cancer cells and acquire features that resemble immunological memory. However, tumour-memory NK cells remain far less studied. Here, I generated memory-NK cells by cytokine and tumour-priming to find commonalities, and better define the nature of NK cell “memory” in vitro and, for the first time, in vivo. TpNK cells showed increased cytotoxicity against multiple tumour cell lines in vitro, analogous to CIML-NK cells. Multidimensional cytometry identified distinct memory-like profiles of subsets of cells with memory-like characteristics; upregulation of CD57, CD69, CD25 and ICAM1. Proteomic profiling identified 170 proteins restricted to TpNK cells, including proteins involved in mitochondrial survival, which translated into enhanced metabolic function. NK cell homotypic interactions were studied as a potential mechanism of activation, providing preliminary evidence that TpNK cells engage in homotypic interactions with autologous NK cells and potentially activate NK cells in a homotypical manner. Finally, I provide evidence of the generation of tumour-memory NK cells in patients with myeloid leukaemias both in vitro and in vivo as part of a clinical trial (NCT05933070). The patients’ NK cells present a phenotype akin to the one described in healthy donors previously and display enhanced cytotoxic capacity and persistence over time, all in keeping with the characteristics of tumour-memory NK cells. To my knowledge, an in-depth characterisation of the effects of tumour-priming in the generation of tumour-memory NK cells has not been done and highlights the importance of further understanding tumour-memory NK cells for their important implications in the context of cancer immunotherapy.

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