Steroid-producing immune cells promote metastatic dissemination of cancer cells

产生类固醇的免疫细胞促进癌细胞的转移扩散

• 批准号: MR/V028995/1
• 负责人: Bidesh Mahata
• 金额: $ 60.26万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV028995%2F1
• 关键词: Steroid; producing; immune; cells; promote

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.

转移是癌症死亡的主要原因，肺是一个常见的受影响器官。为了定殖远端器官，循环肿瘤细胞必须克服许多障碍，例如在循环中存活，浸润和传播远端组织，逃避抗肿瘤免疫，作为潜在的肿瘤引发种子适应和存活，并最终爆发以取代宿主组织。免疫细胞在这个动态而复杂的过程中发挥着双重作用。它们可以破坏癌细胞，也可以促进转移。我们才刚刚开始了解免疫细胞促进转移的机制。目前的治疗经常不能提供针对转移性癌症的持久反应。免疫疗法显示出巨大的希望，但成功有限。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殖的关键分子机制至关重要。以前，我观察到免疫细胞类固醇生成促进癌细胞转移到肺部。然而，T细胞类固醇生成如何有助于癌细胞转移尚不清楚。因此，该项目旨在研究类固醇产生免疫细胞在促进癌症转移中的作用，以及如何在治疗上利用这一点。我们的第一个目标是确定癌细胞转移过程中免疫细胞介导的类固醇生物合成。我们将使用完善的肺转移小鼠模型。我们将鉴定出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中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（即转移性癌细胞的肺定殖）。以前，我们观察到抑制免疫细胞类固醇生成限制肺转移。在这里，我们将测试转移的限制是否是因为抗肿瘤免疫的刺激。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。如果是这样的话，那么我们将确认类固醇调节机制的参与，驱动transferation.Our最终目标是利用类固醇生物合成和信号通路的知识，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，我们将确定这种肺转移的限制是因为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细胞进行基因工程改造，使它们对类固醇产生抗药性。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。将在临床前小鼠模型和体外肿瘤球体共培养模型中测试类固醇抗性T细胞的功效。