Using MHC class I peptides to modulate NK cell activity, as a basis for immunotherapy

自然杀伤（NK）细胞是免疫系统的细胞，可以对抗感染和癌症。它们的反应由许多细胞表面受体控制，包括杀伤细胞免疫球蛋白样受体（KIR）。有许多不同的KIR，但广泛的研究表明，NK细胞和特定的KIR基因可以是决定两种感染（如HIV和丙型肝炎）以及癌症（包括白血病和肝癌）结果的重要因素。迄今为止，由于缺乏对NK细胞生物学的理解，利用NK细胞的特定亚群用于治疗益处一直是困难的。这意味着基于NK细胞的疗法相对粗糙，并且没有考虑到不同NK细胞表达可能仅在特定疾病中相关的不同细胞表面受体的事实。例如，基因KIR2DL3与预防丙型肝炎有关，基因KIR2DS2与非小细胞肺癌治疗的更好反应有关。我们小组的工作开创了NK细胞反应性如何通过细胞表面表达的小肽改变。该项目的目的是发展我们的想法，以便获得治疗试剂。我们将通过靶向KIR2DL3和KIR2DS2基因，并鉴定特异性结合这些受体以激活NK细胞的肽来实现这一点。我们还将寻找可以激活KIR3DS1阳性NK细胞的肽。这一点很重要，因为KIR3DS1与预防艾滋病毒感染以及预防肝癌的发展有关。虽然许多活动都集中在艾滋病毒上，但肝癌仍然是全球主要的健康问题（它是第六常见的癌症），并且令人担忧的是在英国正在增加。重要的是，它很难治疗，目前只有一种化学治疗试剂被许可用于这种情况。在确定了我们可以用来激活NK细胞的关键肽之后，我们将在体外使用它们来激活NK细胞。我们将设计最佳策略来表达所鉴定的肽，然后优化培养大量表达相关受体的NK细胞所需的培养条件。到项目结束时，我们希望有一种适合治疗用途的试剂，根据研究结果，它可能直接适用于I期研究。

Natural killer (NK) cells are cells of the immune system that can fight infections and cancer. Their responses are controlled by a number of cell surface receptors including the killer cell immunoglobulin-like receptors (KIR). There are many different KIR but extensive studies have shown that NK cells and specific KIR genes can be important factors in determining the outcome of both infections, such as HIV and hepatitis C, and also of cancers, including leukaemia and liver cancer. To date harnessing specific sub-populations of NK cells for therapeutic benefit has been difficult because of a lack of understanding of NK cell biology. This has meant that NK cell based therapies are relatively crude and do not take account of the fact that different NK cells express different cell-surface receptors that may be relevant only in specific diseases. For instance the gene KIR2DL3 is associated with protection against hepatitis C, and the gene KIR2DS2 is associated with a better response to treatment in non-small cell lung cancer.Work in our group has pioneered how NK cell reactivity can be altered by small peptides expressed on the surface of cells. The aim of this project is to develop our ideas so that a therapeutic reagent can be obtained. We will do this by targeting both the KIR2DL3 and KIR2DS2 genes, and identifying peptides that specifically bind these receptors to activate NK cells. We will also look for peptides that can activate KIR3DS1-positive NK cells. This is important because KIR3DS1 is associated with protection against HIV infection and also against the development of liver cancer. Whilst much activity has been focused on HIV, liver cancer continues to be a major health problem worldwide (it is the 6th commonest cancer), and alarmingly is on the increase in the UK. Importantly it is difficult to treat, and there is only one chemotherapeutic reagent currently licensed for this condition. Having identified key peptides that we can use to activate NK cell, we will then use them in vitro to activate NK cells. We will devise optimal strategies for expressing the identified peptides and then optimising the culture conditions necessary for growing large numbers of NK cells expressing the relevant receptor. By the end of the project we hope to have a reagent suitable for therapeutic use, which depending on the results of the investigation maybe directly suitable for phase I studies.