Investigation into next generation immunotherapy candidates and the anti-tumour immune response

描述工作的背景，包括在主管自己的团队中进行的工作和以前的工作。[This信息将被评论者用来理解所提出的研究的背景] TAMs是癌症中最丰富的基质细胞群之一。"基质“描述了正常非癌细胞的异质集合，这些细胞被招募到肿瘤微环境中并促进癌症进展。巨噬细胞被肿瘤劫持，以帮助支持血管生成，免疫和化疗抑制，以及肿瘤细胞migration.Our实验室已经表征了TAM的亚群，其通过血红素加氧酶-1（HO-1）的表达在肿瘤微环境中具有有效的免疫抑制功能。Arnold实验室在ClinicalCancer Research（2018）上发表了一篇论文，证明使用一种名为锡中卟啉（SnMP）的HO-1小分子抑制剂靶向这些巨噬细胞中的HO-1活性，可用于提高化疗引发的免疫反应的有效性，以控制肿瘤生长。因此，免疫刺激化疗和SnMP的组合代表了一种新的免疫疗法组合。化疗用于治疗癌症已有近70年的历史。这些分子首先被用于癌症患者，因为它们具有靶向细胞周期的能力。然而，化疗也可以作为免疫疗法，通过引发抗肿瘤CD 8 + T细胞并引发其浸润到肿瘤微环境中来刺激免疫监视。由于细胞毒性化疗广泛应用于临床，它们代表了SnMP或其他Ho-1抑制剂的适当配对，可用于I期试验。然而，SnMP确实有缺点，这可能会阻碍其在后期试验中的长期进展，因为SnMP不能口服给患者，抑制HO-1和HO-2，并且因为它是一种通用化合物而没有知识产权的机会。因此，本项目旨在开发新一代HO-1抑制剂，用于临床转化为新型免疫治疗药物。本项目的目的是重新设计一种口服选择性HO-1抑制剂，我们将验证其临床前疗效，并生成用于临床转化的数据包，以及进一步研究HO-1在癌症进展中的作用的工具。我们还假设，一些已经在临床上使用的药物实际上可能对调节HO-1活性具有脱靶效应，这些将使用计算机筛选方法进行探索和预测，并使用为主要项目目标建立的测定方法进行验证。

Describe background to the work including that carried out in the supervisor's own team and previous work. [This informationwill be used by the reviewers to understand the context of the proposed study].TAMs are one of the most abundant stromal cell populations in cancer. The 'stroma' describes the heterogeneous collection ofnormal non-cancerous cells which get recruited into the tumour microenvironment and facilitate cancer progression. Macrophagesget hijacked by the tumour to help support angiogenesis, immune and chemotherapeutic suppression, and tumour cell migration.Our laboratory has characterised a subpopulation of TAMs which have potent immune suppressive functions in the tumourmicroenvironment through their expression of the enzyme heme oxygenase-1 (HO-1). Arnold lab published a paper in ClinicalCancer Research (2018) that demonstrated using a small molecule inhibitor for HO-1 called tin mesoporphyrin (SnMP) to targetthe HO-1 activity in these macrophages could be used to improve the efficacy of a chemotherapy-elicited immune response tocontrol tumour growth. As such, the combination of an immune-stimulating chemotherapy and SnMP represented a novelimmunotherapy combination. Chemotherapy has been utilised for the treatment of cancer for nearly 70 years. These moleculeswere first administered to patients with cancer for their ability to target the cell cycle. However, chemotherapy can also act as animmunotherapy, stimulating immune surveillance through both priming anti-tumour CD8+ T cells and eliciting their infiltration intothe tumour microenvironment. As cytotoxic chemotherapies are widely used in the clinic, they represent an appropriate pairingfor SnMP, or other Ho-1 inhibitor, to take into a phase I trial. However, SnMP does have drawbacks that could hinder its long-termprogress through later phase trials as SnMP cannot be delivered orally to the patient, inhibits both HO-1 and HO-2 and has noopportunity for intellectual property as it is a generic compound. As such, the current project aims to develop the next generation of HO-1 inhibitors for clinical translation as novel immunotherapeutics.The Aim of this project is to redesign an orally available selective HO-1 inhibitor which we will validate for preclinical efficacy andgenerate a data-package for clinical translation as well as a tool to further investigating the role of HO-1 in cancer progression. We also hypothesise that some drugs already used in the clinic may actually have off-target effects on modulating HO-1 activityand these will be explored and predicted using in silico screening approaches and validated using the assays that will establishedfor the primary project goal.