Steroid-producing immune cells promote metastatic dissemination of cancer cells

点击翻译按钮获取中文摘要

Metastasis is the leading cause of death in cancer, with the lung being a commonly affected organ. To colonise distant organs, circulating tumour cells must overcome numerous obstacles such as surviving in the circulation, infiltrating and disseminating distant tissue, evading anti-tumour immunity, adapting and surviving as latent tumour-initiating seeds and eventually breaking out to replace the host tissue. Immune cells play a dual role during this dynamic and complicated process. They can destroy the cancer cells, as well as, can promote the metastasis. We are only beginning to understand the mechanisms of immune cell promotion of metastasis. Current treatments frequently fail to provide durable responses against metastatic cancers. Immunotherapies showed great promise but with limited success. Therefore, to develop better immunotherapies, further studies revealing the critical molecular mechanisms driving metastatic colonisation are essential. Previously, I observed that immune cell steroidogenesis promotes metastatic dissemination of cancer cells to the lung. Yet, how T cell steroidogenesis contributes to the cancer cell metastasis is unknown. Therefore, this project has been designed to investigate the role of steroid-producing immune cells in the promotion of cancer metastasis and how this may be exploited therapeutically. Our first aim is to define the immune cell-mediated steroid biosynthesis during metastasis of cancer cells. We will use well-established mice models of lung metastasis. We will identify and characterise steroid-producing immune cells. We will determine where and how they originate. We will measure what steroids they produce. We aim to reveal the signalling cues that induce steroid biosynthesis in immune cells during metastasis. In next, we will determine how do steroid-producing immune cells promote metastasis of cancer cells (i.e. lung colonisation of metastatic cancer cells). Previously, we observed that inhibition of immune cell steroidogenesis restricts lung metastasis. Here we will test whether the restriction of metastasis is because of stimulation of the anti-tumour immunity. We will examine the number and functionality of different immune cells such as T cells, natural killer cells, regulatory T cells and macrophages. Alternatively, we will test whether the steroids (synthesised by immune cells) directly promote the lung metastasis. If so, then we will confirm the involvement of the steroid regulatory mechanisms that drive metastasis.Our ultimate aim is to exploit this knowledge of steroid biosynthesis and signalling pathway to innovate therapeutic strategy for metastatic cancer. Our first approach is to restrict metastasis by using pharmacologic inhibitors of the immune cell-mediated steroid production pathway. In mice model, we will test whether the administration of these inhibitors restricts cancer metastasis. Next, we will determine whether this restriction of lung metastasis is because of stimulation of anti-tumour immunity or a direct effect on tumour cells. Our next innovative approach is to develop therapeutic steroid-resistant T cells, both in human and mice. We will genetically engineer the T cells to make them steroid-resistant. For example, we will delete the steroid receptor by genetic engineering or introduce a transgene that blocks steroid signalling. The efficacy of the steroid-resistant T cells will be tested in the preclinical mice model and in an in vitro tumour spheroid co-culture model.