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
基本信息
- 批准号:MR/W018454/1
- 负责人:
- 金额:$ 80.18万
- 依托单位:
- 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:
- 关键词:
项目摘要
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.
癌症是全世界疾病和死亡的主要原因。据估计,2020 年将有 1,930 万新发癌症病例和 1,000 万人死亡。癌症死亡之前往往会经历长期患病,给患者和护理人员带来痛苦。迫切需要改进癌症治疗方法。 T 细胞是一种特殊的免疫细胞,可以识别并杀死癌细胞,但它们的功能通常在肿瘤中通过一种称为癌症免疫抑制的过程而受到抑制。使用针对所谓的免疫检查点 CTLA-4 和 PD-L1 的药物将 T 细胞从免疫抑制中释放出来,可以在一些接受治疗的患者中产生非常有效的临床反应。然而,这些疗法仅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疗法的早期成功的基础上为大多数目前没有反应的患者造福,就需要确定在癌症中抑制免疫系统的其他方法。我们实验室进行的研究发现,T 细胞内有一种新的抑制途径,该途径依赖于一种名为 Rho 鸟嘌呤核苷酸交换因子 1 (ARHGEF1) 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。 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 如何抑制癌症免疫和免疫治疗反应,了解 T 细胞接收到的驱动其抑制功能的信号,并确定如何靶向 ARHGEF1 通路来改善癌症治疗。 我们提出的研究分为三个目标:首先,使用允许 ARHGEF1 在 T 细胞内被破坏的新小鼠遗传模型,我们将测试 ARHGEF1 如何发挥作用来抑制对原发性和转移性实体癌的免疫反应。我们将测试 ARHGEF1 的靶向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产生协同作用。 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,我们将定义激活小鼠和人类T细胞中ARHGEF1抑制功能的细胞外信号和受体,从而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,限制对癌症的免疫和免疫治疗反应。该研究将确定开发新免疫疗法的分子靶标,这些疗法单独或与现有免疫检查点抑制剂联合作用,以改善癌症患者的治疗结果。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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
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Rahul Roychoudhuri其他文献
Rahul Roychoudhuri的其他文献
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{{ truncateString('Rahul Roychoudhuri', 18)}}的其他基金
IMMUNOREG: Memory of Self: Maintenance and memory of immunoregulatory responses
IMMUNOREG:自我记忆:免疫调节反应的维持和记忆
- 批准号:
EP/X024709/1 - 财政年份:2023
- 资助金额:
$ 80.18万 - 项目类别:
Research Grant
Cellular and molecular organisation of long-lived immunoregulatory responses within the lung
肺内长效免疫调节反应的细胞和分子组织
- 批准号:
BB/X006344/1 - 财政年份:2023
- 资助金额:
$ 80.18万 - 项目类别:
Research Grant
Molecular regulation of NK cell functional maturation by the transcription factor BACH2
转录因子 BACH2 对 NK 细胞功能成熟的分子调节
- 批准号:
MR/S024468/2 - 财政年份:2020
- 资助金额:
$ 80.18万 - 项目类别:
Research Grant
Molecular regulation of NK cell functional maturation by the transcription factor BACH2
转录因子 BACH2 对 NK 细胞功能成熟的分子调节
- 批准号:
MR/S024468/1 - 财政年份:2019
- 资助金额:
$ 80.18万 - 项目类别:
Research Grant
Orchestration of PI3K-dependent transcriptional programmes by the transcription factor BACH2
转录因子 BACH2 协调 PI3K 依赖性转录程序
- 批准号:
BB/N007794/1 - 财政年份:2016
- 资助金额:
$ 80.18万 - 项目类别:
Research Grant
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