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

了解并靶向 ARHGEF1 通路的抑制功能，以释放 T 细胞免疫来对抗癌症

• 批准号: MR/W018454/1
• 负责人: Rahul Roychoudhuri
• 金额: $ 80.18万
• 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%2FW018454%2F1
• 关键词: Understanding; targeting; suppressive; function; ARHGEF1

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.

癌症是全球疾病和死亡的主要原因。估计有1,930万例新的癌症病例，2020年死亡1000万例。癌症死亡通常是长时间的疾病，导致患者和看护者的困扰。迫切需要改善癌症治疗方法。 T细胞是可以识别和杀死癌细胞的专门免疫细胞，但是通过称为癌症免疫抑制的过程，它们的功能通常在肿瘤中抑制。使用针对所谓免疫检查点CTLA-4和PD-L1的药物从免疫抑制中释放T细胞，导致一些接受治疗的患者的临床反应非常有效。但是，这些疗法仅导致少数癌症患者和类型的癌症的持久反应。如果我们要以早期的癌症免疫疗法成功为基础，为了使大多数目前没有反应的患者受益，那么有必要确定免疫系统在癌症中受到抑制的其他方式。在我们的实验室内进行的研究确定了在T细胞中运行的新抑制途径，取决于一种称为Rho Guanine核苷酸交换因子1（ARHGEF1）的信号蛋白，该途径限制了T细胞功能并限制了其消除癌症的能力。 ARHGEF1的抑制功能还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如何抑制对癌症和免疫疗法反应的免疫力，以了解T细胞收到的信号，这些信号驱动其抑制作用，并确定如何针对ARHGEF1途径以改善癌症治疗。 我们提出的研究分为三个目的：首先，使用允许ARHGEF1在T细胞中破坏ARHGEF1的新小鼠遗传模型，我们将测试ARHGEF1的功能如何抑制对原发性和转移性固体癌症的免疫反应。我们将测试靶向ARHGEF1是否可以改善收养细胞免疫疗法或与现有的免疫检查点抑制剂治疗癌症的协同作用。 其次，使用尖端的新实验技术来研究分子水平的生物学过程，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T细胞中的功能。 第三，我们将定义细胞外信号和受体，这些信号和受体激活小鼠和人T细胞中ARHGEF1的抑制作用，从而确定了免疫疗法的新靶标。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和免疫疗法反应的免疫力。这项研究将定义分子靶标，用于开发单独起作用或与现有的免疫检查点抑制剂一起起作用，以改善癌症患者的治疗结果。

项目成果

BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis.

• DOI: 10.1084/jem.20211476
• 发表时间: 2022-12-05
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Imianowski, Charlotte J.;Whiteside, Sarah K.;Lozano, Teresa;Evans, Alexander C.;Benson, Jayme D.;Courreges, Christina J. F.;Sadiyah, Firas;Lau, Colleen M.;Zandhuis, Nordin D.;Grant, Francis M.;Schuijs, Martijn J.;Vardaka, Panagiota;Kuo, Paula;Soilleux, Elizabeth J.;Yang, Jie;Sun, Joseph C.;Kurosaki, Tomohiro;Okkenhaug, Klaus;Halim, Timotheus Y. F.;Roychoudhuri, Rahul
• 通讯作者: Roychoudhuri, Rahul