Enhancing cancer immunotherapy through the identification and characterisation of novel T-regulatory cell targets

通过识别和表征新型 T 调节细胞靶标增强癌症免疫治疗

• 批准号: 2458898
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2458898
• 关键词: Enhancing; cancer; immunotherapy; through; identification

Whilst cancer immunotherapies have seen a recent boom in their potential to treat patients with several different late-stage cancer types, the long-term response rates of even the most promising treatments such as ipilimumab and nivolumab (CTLA-4 and PD-1 checkpoint inhibitors, respectively) remain low at around 21%. A strong contributing factor to this is the immunosuppressive nature of the tumour microenvironment (TME). T-regulatory cells (Tregs) are a subset of CD4+ T cells that, under normal physiological conditions, dampen the body's immune responses to self-antigens and thus play an important part in preventing autoimmunity. However, within the TME, this regulatory phenotype can reduce the efficacy of the host's immune response against the tumour, also limiting the effectiveness of many current immunotherapies. Selectively targeting and depleting these tumour Tregs thus becomes an appealing strategy to boost the response rate of current treatments. This project aims to bioinformatically identify novel potential tumour Treg targets by filtering mouse Treg RNA-seq data for genes with suitable characteristics for a therapeutic target. Differential expression, presence on the exterior side of the cell surface and homology to human genes will be investigated to ensure genes are enriched in tumour Tregs and targetable by antibody therapy. These targets will then be tested for cell surface protein expression and evaluated against a library of Treg-binding antibodies developed by an industrial collaborator (BioInvent Intl AB) in vitro, to determine whether any bind to the enriched targets. Those that do bind will then have their binding profiles and depletion capabilities assessed, with promising antibodies then being brought forward into in vivo depletion experiments, followed by tumour therapy experiments both alone and in combination with immune checkpoint blockade.

虽然癌症免疫疗法最近在治疗几种不同晚期癌症类型患者的潜力方面出现了激增，但即使是最有希望的治疗方法，如ipilimumab和nivolumab（分别为CTLA-4和PD-1检查点抑制剂）的长期反应率仍然很低，约为21%。一个强有力的促成因素是肿瘤微环境（TME）的免疫抑制性质。调节性T细胞（T-regulatory cells，T-R）是CD 4 + T细胞的一个亚群，在正常生理条件下，抑制机体对自身抗原的免疫反应，从而在预防自身免疫中发挥重要作用。然而，在TME内，这种调节表型可以降低宿主对肿瘤的免疫应答的功效，也限制了许多当前免疫疗法的有效性。因此，选择性地靶向和消耗这些肿瘤THBG成为提高当前治疗反应率的有吸引力的策略。该项目旨在通过筛选小鼠Treg RNA-seq数据，以生物信息学方法鉴定新的潜在肿瘤Treg靶点，以寻找具有治疗靶点合适特征的基因。将研究差异表达、在细胞表面外侧的存在以及与人基因的同源性，以确保基因在肿瘤细胞中富集并可通过抗体治疗靶向。然后测试这些靶标的细胞表面蛋白表达，并在体外针对由工业合作者（BioInvent Intl AB）开发的Treg结合抗体文库进行评价，以确定是否有任何结合富集的靶标。然后，那些结合的抗体将评估其结合特征和消除能力，然后将有希望的抗体带入体内消除实验，然后进行单独和与免疫检查点阻断相结合的肿瘤治疗实验。