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

虽然癌症免疫疗法最近在治疗几种不同晚期癌症类型的患者方面取得了蓬勃发展，但即使是最有希望的治疗方法，如ipilimumab和nivolumab(分别是CTLA-4和PD-1检查点抑制剂)的长期应答率仍然很低，约为21%。一个强有力的因素是肿瘤微环境(TME)的免疫抑制性质。T调节细胞(Tregs)是CD4+T细胞的一个亚群，在正常生理条件下，它会抑制机体对自身抗原的免疫反应，从而在防止自身免疫方面发挥重要作用。然而，在TME中，这种调节表型会降低宿主对肿瘤的免疫反应的有效性，也限制了目前许多免疫疗法的有效性。因此，选择性地靶向和消耗这些肿瘤Tregs成为一种吸引人的策略，以提高当前治疗的应答率。该项目旨在通过筛选小鼠Treg RNA-seq数据来识别新的潜在肿瘤Treg靶点，以寻找具有适合治疗靶点的特征的基因。将调查差异表达、细胞表面外部的存在以及与人类基因的同源性，以确保基因在肿瘤树中丰富，并可通过抗体治疗进行靶向治疗。然后，这些靶标将被测试细胞表面蛋白的表达，并与工业合作者(BioInventIntl AB)开发的Treg结合抗体库进行体外评估，以确定是否有任何抗体与浓缩的靶标结合。然后，那些确实结合的抗体将被评估其结合情况和耗竭能力，有希望的抗体随后被带进体内耗竭实验，随后是单独和与免疫检查点阻断相结合的肿瘤治疗实验。

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.