Understanding and targeting the suppressive function of the ARHGEF1 pathway to unleash T cell immunity against cancer

癌症是全球疾病和死亡的主要原因。2020年估计有1930万新发癌症病例和1000万死亡病例。癌症死亡之前往往是长时间的疾病，造成痛苦的病人和照顾者。迫切需要改进癌症的治疗方法。 T细胞是一种特殊的免疫细胞，可以识别和杀死癌细胞，但它们的功能通常通过一种称为癌症免疫抑制的过程在肿瘤中受到抑制。使用靶向所谓的免疫检查点CTLA-4和PD-L1的药物将T细胞从免疫抑制中释放出来，在一些接受治疗的患者中产生了非常有效的临床反应。然而，这些疗法只会对少数癌症患者和癌症类型产生持久的反应。如果我们要在癌症免疫治疗的早期成功基础上为大多数目前没有反应的患者带来好处，那么就需要确定癌症中免疫系统被抑制的其他方式。我们实验室进行的研究已经确定了T细胞内运行的一种新的抑制途径，该途径依赖于一种名为Rho鸟嘌呤核苷酸交换因子1（ARHGEF 1）的信号蛋白，该蛋白限制T细胞功能并限制其消除癌症的能力。ARHGEF 1的抑制功能也限制了免疫检查点抑制剂驱动的反应。这项工作的目的是了解ARHGEF 1如何抑制对癌症和免疫治疗反应的免疫力，了解T细胞接收的驱动其抑制功能的信号，并确定如何靶向ARHGEF 1通路以改善癌症治疗。 我们提出的研究分为三个目标：首先，使用新的小鼠遗传模型，允许ARHGEF 1在T细胞内被破坏，我们将测试ARHGEF 1如何发挥作用，抑制对原发性和转移性实体癌的免疫反应。我们将测试靶向ARHGEF 1是否能改善过继性细胞免疫疗法，或与现有的癌症免疫检查点抑制剂疗法协同作用。 其次，使用尖端的新实验技术在分子水平上研究生物过程，我们将研究导致ARHGEF 1抑制T细胞功能的分子相互作用。我们将确定ARHGEF 1在人类T细胞中的功能。 第三，我们将确定激活小鼠和人类T细胞中ARHGEF 1抑制功能的细胞外信号和受体，确定免疫治疗的新靶点。这些研究将定义一种新的抑制途径，该途径在T细胞内发挥作用，以限制对癌症的免疫力和免疫治疗反应。该研究将确定开发新免疫疗法的分子靶点，这些免疫疗法单独或与现有的免疫检查点抑制剂联合作用，以改善癌症患者的治疗效果。

Cancer is a leading cause of illness and death worldwide. There were an estimated 19.3 million new cases of cancer and 10.0 million deaths in 2020. Cancer death is often preceded by prolonged periods of illness causing distress to patients and carers. There is an urgent need for improved treatments for cancer. T cells are specialised immune cells that can recognise and kill cancer cells but their function is often suppressed in tumours through a process known as cancer immunosuppression. Releasing T cells from immune suppression using medicines that target the so-called immune checkpoints, CTLA-4 and PD-L1, results in very effective clinical responses in some patients receiving treatment. However, these therapies only result in long-lasting responses in a minority of cancer patients and types of cancer. There is a need to identify other ways the immune system is suppressed in cancer if we are to build upon early successes in cancer immunotherapy for the benefit of the majority of patients who presently do not respond. Research conducted within our laboratories has identified a new suppressive pathway operating within T cells, dependent upon a signalling protein called Rho Guanine Nucleotide Exchange Factor 1 (ARHGEF1) which restricts T cell function and limits their ability to eliminate cancer. The suppressive function of ARHGEF1 also limits responses driven by immune checkpoint inhibitors. The purpose of this work is to understand how ARHGEF1 suppresses immunity to cancer and immunotherapy responses, to understand the signals received by T cells which drive its suppressive function, and to determine how the ARHGEF1 pathway can be targeted to improve cancer therapy. Our proposed research is organised into three aims: Firstly, using new mouse genetic models allowing ARHGEF1 to be disrupted within T cells, we will test how ARHGEF1 functions to suppress immune responses to primary and metastatic solid cancers. We will test whether targeting of ARHGEF1 improves adoptive cell immunotherapy or synergises with existing immune checkpoint inhibitor therapies for cancer. Secondly, using cutting-edge new experimental techniques for studying biological processes at the molecular level, we will look at the molecular interactions that cause ARHGEF1 to suppress T cell functions. We will determine the function of ARHGEF1 in human T cells. Thirdly, we will define the extracellular signals and receptors which activate the suppressive function of ARHGEF1 in mouse and human T cells, identifying new targets for immunotherapy. These studies will define a new suppressive pathway which operates within T cells to limit immunity to cancer and immunotherapy responses. The research will define molecular targets for development of new immunotherapies that act alone or in conjunction with existing immune checkpoint inhibitors to improve therapeutic outcomes for patients with cancer.