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

巨噬细胞是一种在肿瘤微环境（TME）中大量存在的先天免疫细胞，具有多种表型，包括“抗肿瘤”和“促肿瘤”。它们可以通过直接杀伤癌细胞或通过抗体依赖细胞介导的细胞毒性（ADCC）发挥抗肿瘤活性。自然杀伤细胞（NK）也是先天免疫细胞，具有强大的抗肿瘤功能，包括直接裂解靶肿瘤细胞和ADCC。它们的功能由种系编码受体控制，包括杀伤细胞免疫球蛋白样受体（KIRs），其中一种被称为KIR2DS2，与有益的癌症结果和许多实体肿瘤的识别有关。Khakoo实验室已经开发出表达KIR2DS2的MHC配体肽的DNA疫苗，这些疫苗已被证明可以增强体内的抗肿瘤反应。巨噬细胞在TME中与NK细胞相互作用，改变其表型状态可以增强NK细胞的细胞毒性。然而，研究巨噬细胞对NK细胞的抗原递呈能力的研究有限，DNA疫苗的研究尚未确定其对其他免疫细胞的影响。因此，博士学位的目的是探索暴露于巨噬细胞的NK细胞的激活和细胞毒性，巨噬细胞已被操纵以呈现KIR2DS2激活肽。目前，研究巨噬细胞对NK细胞刺激影响的共培养体系已经建立。在未来的实验中，这将用于监测NK细胞与转染了DNA构建体的巨噬细胞一起培养时活化的变化。

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.