Steroid-producing immune cells promote metastatic dissemination of cancer cells

转移是癌症死亡的主要原因，而肺是一个常见的受累器官。为了在远处器官定植，循环中的肿瘤细胞必须克服许多障碍，如在循环中存活，渗透和传播远处组织，逃避抗肿瘤免疫，适应和存活为潜在的启动肿瘤的种子，并最终爆发以取代宿主组织。在这个动态而复杂的过程中，免疫细胞扮演着双重角色。它们可以摧毁癌细胞，也可以促进癌细胞的转移。我们才刚刚开始了解免疫细胞促进肿瘤转移的机制。目前的治疗方法往往不能对转移性癌症产生持久的反应。免疫疗法显示出巨大的前景，但收效甚微。因此，为了开发更好的免疫疗法，进一步研究驱动转移定植的关键分子机制是必不可少的。在此之前，我观察到免疫细胞类固醇的生成促进了癌细胞向肺部的转移扩散。然而，T细胞类固醇激素的生成对癌细胞转移的影响尚不清楚。因此，该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，以及如何利用这一作用进行治疗。我们的第一个目标是定义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方式。我们将测量它们产生的类固醇。我们的目标是揭示在转移过程中诱导免疫细胞类固醇生物合成的信号线索。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(即转移癌细胞的肺部定植)。以前，我们观察到免疫细胞类固醇合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因为刺激了抗肿瘤免疫。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。如果是这样的话，我们将证实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类固醇生物合成和信号通路的知识来创新转移癌症的治疗策略。我们的第一个方法是通过使用免疫细胞介导的类固醇产生途径的药物抑制剂来限制转移。在小鼠模型中，我们将测试这些抑制剂的使用是否限制了癌症的转移。接下来，我们将确定这种对肺转移的限制是因为刺激了抗肿瘤免疫，还是直接作用于肿瘤细胞。我们的下一个创新方法是在人类和小鼠身上开发治疗类固醇耐药的T细胞。我们将对T细胞进行基因改造，使其对类固醇具有抵抗力。例如，我们将通过基因工程删除类固醇受体，或者引入阻止类固醇信号的转基因。抗类固醇T细胞的有效性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.