Enhancing T cell immunity to cancer metastasis

转移性癌症是单个细胞从原发肿瘤逃逸到身体远端的结果。癌症转移过程导致了90%以上的癌症死亡。一个例子是皮肤癌黑色素瘤，细胞可能会移位并转移到肝脏或肺。在这项建议中，我们已经确定了T细胞内的一条生化途径，当被激活时，促进了极强的免疫介导的肺转移排斥反应。生化途径是由一种名为PI3K的酶激活的。临床上使用了几种药物来抑制这一途径，其中一些已经被用来刺激免疫系统。在这里，我们提出了需要激活该通路的情况。这项建议的目的是了解PI3K的过度激活如何导致癌症转移的消除，并利用这一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细胞介导的消除肺癌的机制。我们将确定辅助T细胞参与抗癌的其他免疫亚型。AIM 2探索了一种我们已经发现的新的生化途径，利用现有的药物，如阿司匹林，可以在T细胞中释放强大的PI3K活性。这项研究主要集中在使用临床前小鼠模型来建立我们已经发现的显著的抗转移肿瘤反应的潜在机制。这些数据将通过我们与Add Aspirin试验(http://www.addaspirintrial.org/).)的合作链接与癌症患者的原始人类数据进行比较这项研究将使新一代基于免疫的抗转移疗法的开发成为可能，这种疗法旨在防止那些被诊断和治疗了早期癌症但有转移风险的患者成功地发生转移。

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.