Steroid-producing immune cells promote metastatic dissemination of cancer cells

转移是癌症死亡的主要原因，肺是最常见的受累器官。为了在远端器官中定植，循环肿瘤细胞必须克服许多障碍，如在循环中存活，浸润和传播远端组织，逃避抗肿瘤免疫，作为潜伏的肿瘤启动种子适应和存活，并最终突破取代宿主组织。免疫细胞在这一动态复杂的过程中起着双重作用。它们既能消灭癌细胞，又能促进癌细胞的转移。我们才刚刚开始了解免疫细胞促进转移的机制。目前的治疗方法经常不能对转移性癌症提供持久的反应。免疫疗法显示出巨大的希望，但成效有限。因此，为了开发更好的免疫疗法，进一步研究揭示驱动转移性定植的关键分子机制是必不可少的。以前，我观察到免疫细胞类固醇生成促进癌细胞转移扩散到肺部。然而，T细胞甾体生成如何促进癌细胞转移尚不清楚。因此，本项目旨在研究产生类固醇的免疫细胞在促进癌症转移中的作用，以及如何利用这种作用进行治疗。我们的第一个目标是确定在癌细胞转移过程中免疫细胞介导的类固醇生物合成。我们将使用成熟的小鼠肺转移模型。我们将鉴定和鉴定产生类固醇的免疫细胞。我们将确定它们的来源和来源。我们将测量它们产生的类固醇。我们的目的是揭示免疫细胞在转移过程中诱导类固醇生物合成的信号信号。接下来，我们将确定产生类固醇的免疫细胞如何促进癌细胞的转移（即转移癌细胞的肺定植）。先前，我们观察到免疫细胞类固醇生成的抑制限制了肺转移。在这里，我们将测试转移的限制是否是由于抗肿瘤免疫的刺激。我们将检查不同免疫细胞的数量和功能，如T细胞、自然杀伤细胞、调节性T细胞和巨噬细胞。或者，我们将测试类固醇（由免疫细胞合成）是否直接促进肺转移。如果是这样，那么我们将确认驱动转移的类固醇调节机制的参与。我们的最终目标是利用这些类固醇生物合成和信号通路的知识来创新转移性癌症的治疗策略。我们的第一种方法是通过使用免疫细胞介导的类固醇产生途径的药理学抑制剂来限制转移。在小鼠模型中，我们将测试这些抑制剂的施用是否限制癌症转移。接下来，我们将确定这种对肺转移的限制是由于抗肿瘤免疫的刺激还是对肿瘤细胞的直接影响。我们的下一个创新方法是在人类和小鼠中开发治疗性类固醇抗性T细胞。我们将对T细胞进行基因改造，使它们能抵抗类固醇。例如，我们将通过基因工程删除类固醇受体或引入阻断类固醇信号传导的转基因。类固醇抵抗T细胞的功效将在临床前小鼠模型和体外肿瘤球体共培养模型中进行测试。

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.