Investigating the interaction between macrophages and natural killer cells in the tumour microenvironment.

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Macrophages are innate immune cells that are abundant in the tumour microenvironment (TME) and display a range of phenotypes, including 'anti-tumour' and 'pro-tumour'. They can exert anti-tumour activities through direct killing of cancerous cells or by antibody-dependent cell-mediated cytotoxicity (ADCC). Natural killer (NK) cells are also innate immune cells and have potent anti-tumour functions including the direct lysis of target tumour cells and ADCC. Their function is governed by germline-encoded receptors, including killer cell immunoglobulin-like receptors (KIRs), one of which, known as KIR2DS2, is associated with beneficial cancer outcomes and the recognition of many solid tumours. The Khakoo laboratory has developed DNA vaccines expressing a peptide:MHC ligand for KIR2DS2 and these have been shown to enhance anti-tumour responses in vivo. It is well established that macrophages interact with NK cells in the TME and that altering their phenotypic state can boost NK cell cytotoxicity. However, there are limited studies investigating the antigen presentation abilities of macrophages towards NK cells and the DNA vaccine research has not determined the impact on other immune cells. Consequently, the aim of the PhD is to explore the activation and cytotoxicity of NK cells that are exposed to macrophages which have been manipulated to present the KIR2DS2 activating peptides. So far, a co-culture system for studying the influence of macrophages on NK cell stimulation has been established. In future experiments, this will be used to monitor changes in activation when NK cells are cultured with macrophages that have been transfected with the DNA constructs.