Enhancing T cell immunity to cancer metastasis

增强T细胞对癌症转移的免疫力

• 批准号: MR/Y013301/1
• 负责人: Klaus Okkenhaug
• 金额: $ 317.71万
• 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: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013301%2F1
• 关键词: Enhancing; cell; immunity; cancer; metastasis

Metastatic cancer results from the escape of individual cells from the primary tumour to distal parts of the body. The process of cancer metastasis is responsible for more than 90% of cancer deaths. One example is the skin cancer melanoma from which cells can become dislodged and travel to the liver or lung. In this proposal, we have identified a biochemical pathway within T cells which when activated, promotes extremely potent immune-mediated rejection of lung metastases. The biochemical pathway is activated by an enzyme called PI3K. There are several drugs used in the clinic that inhibit this pathway and some of these have been used to stimulate the immune system. Here we propose circumstances where the pathway instead needs to be activated. The aims of this proposal are to understand how hyperactivation of PI3K leads to the elimination of cancer metastases and to exploit this knowledge to improve immunity to cancer metastases. Our work is organised into two Aims:Aim 1 will find out the mechanism of helper T cell-mediated elimination of lung tumours. We will determine what other immune subtypes the helper T cells engage in the fight against cancer.Aim 2 explores a novel biochemical pathway we have discovered that can unleash potent PI3K activity in T cells using available drugs such as aspirin.This research is mainly focused on the use of preclinical mouse models to establish the underlying mechanisms of the remarkable anti-metastatic tumour responses we have uncovered. These data will be compared to primary human data from cancer patients through our collaborative links with the Add Aspirin trial (http://www.addaspirintrial.org/). This research will enable development of a new generation of anti-metastatic immune-based therapies which aim to prevent successful development of metastases in patients who have been diagnosed and treated with early cancer but who are at risk of metastasis.

转移性癌症是由单个细胞从原发肿瘤逃逸到身体远端部位引起的。 90%以上的癌症死亡是由癌症转移过程造成的。皮肤癌黑色素瘤就是一个例子，其中的细胞可能会脱落并转移到肝脏或肺部。在这项提议中，我们确定了 T 细胞内的一条生化途径，该途径被激活后，可促进极其有效的免疫介导的肺转移排斥反应。该生化途径由一种称为 PI3K 的酶激活。临床上使用了多种药物来抑制这一途径，其中一些已用于刺激免疫系统。在这里，我们提出了需要激活该途径的情况。该提案的目的是了解 PI3K 的过度激活如何导致癌症转移的消除，并利用这些知识来提高对癌症转移的免疫力。我们的工作分为两个目标：目标 1 将找出辅助 T 细胞介导的肺部肿瘤消除机制。我们将确定辅助 T 细胞参与对抗癌症的其他免疫亚型。目标 2 探索了一种新的生化途径，我们发现该途径可以使用阿司匹林等现有药物在 T 细胞中释放有效的 PI3K 活性。这项研究主要集中于使用临床前小鼠模型来建立我们发现的显着抗转移肿瘤反应的潜在机制。这些数据将通过我们与添加阿司匹林试验 (http://www.addaspirintorial.org/) 的合作链接与来自癌症患者的主要人体数据进行比较。这项研究将有助于开发新一代抗转移免疫疗法，旨在防止已诊断并接受早期癌症治疗但有转移风险的患者成功发生转移。