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

癌症是世界范围内疾病和死亡的主要原因。据估计，2020年新增癌症病例1,930万例，死亡1,000万例。癌症死亡之前，往往会有长时间的疾病，给患者和照顾者带来痛苦。目前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，但在肿瘤中，它们的功能通常会通过一种称为癌症免疫抑制的过程受到抑制。使用针对所谓免疫检查点的药物CTLA-4和PD-L1释放免疫抑制的T细胞，在一些接受治疗的患者中产生非常有效的临床反应。然而，这些疗法只对少数癌症患者和癌症类型产生长期反应。如果我们要在癌症免疫治疗的早期成功的基础上，造福于目前没有反应的大多数患者，就需要确定在癌症中抑制免疫系统的其他方式。我们实验室内进行的研究发现了一种在T细胞内运行的新的抑制途径，依赖于一种名为Rho鸟嘌呤核苷酸交换因子1(ARHGEF1)的信号蛋白，该蛋白限制T细胞的功能并限制其消除癌症的能力。ARHGEF1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ARHGEF1是如何抑制对癌症的免疫和免疫治疗反应的，了解驱动其抑制功能的T细胞收到的信号，并确定如何针对ARHGEF1途径来改善癌症治疗。我们建议的研究有三个目标：首先，使用新的小鼠遗传模型，允许ARHGEF1在T细胞内被破坏，我们将测试ARHGEF1如何发挥作用，抑制对原发和转移性实体癌的免疫反应。我们将测试ARHGEF1的靶向是改善过继细胞免疫治疗，还是与现有的癌症免疫检查点抑制疗法协同作用。其次，利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ARHGEF1抑制T细胞功能的分子相互作用。我们将确定ARHGEF1在人类T细胞中的功能。第三，我们将确定激活小鼠和人T细胞中ARHGEF1抑制功能的细胞外信号和受体，为免疫治疗寻找新的靶点。这些研究将定义一种新的抑制途径，该途径在T细胞内运行，以限制对癌症的免疫和免疫治疗反应。这项研究将确定开发新的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一起作用，以改善癌症患者的治疗结果。

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.