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

描述工作的背景，包括主管自己团队中开展的工作和以前的工作。[这些信息将被评价者用来理解拟议研究的背景]。TAM是癌症中最丰富的基质细胞群之一。“间质”描述了正常非癌症细胞的异质集合，这些细胞被招募到肿瘤微环境中，促进癌症的发展。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迁移。我们的实验室鉴定了TAM的一个亚群，它们通过表达血红素加氧酶-1(HO-1)在肿瘤微环境中具有强大的免疫抑制功能。Arnold实验室在《临床癌症研究》(2018)上发表了一篇论文，证明使用HO-1的小分子抑制剂锡中卟啉(SNMP)来靶向这些巨噬细胞中的HO-1活性可以用来提高化疗引发的免疫反应的有效性，以控制肿瘤的生长。因此，免疫刺激化疗和SNMP的结合代表了一种新的免疫疗法组合。近70年来，化疗一直被用于癌症的治疗。这些分子最初用于癌症患者，是因为它们有能力靶向细胞周期。然而，化疗也可以起到免疫治疗的作用，通过启动抗肿瘤CD8+T细胞和诱导它们渗透到肿瘤微环境来刺激免疫监视。随着细胞毒性化疗药物在临床上的广泛应用，它们是SNMP或其他HO-1抑制剂进入I期试验的合适组合。然而，SNMP确实存在缺陷，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，同时抑制HO-1和HO-2，而且由于它是一种仿制化合物，没有获得知识产权的机会。因此，目前的项目旨在开发下一代HO-1抑制剂作为新的免疫疗法用于临床翻译。该项目的目的是重新设计一种口服可用的选择性HO-1抑制剂，我们将验证其临床前有效性，并生成用于临床翻译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，一些已经用于临床的药物实际上可能对调节HO-1活性具有非靶点效应，这些药物将在计算机筛查方法中进行探索和预测，并使用将为主要项目目标建立的分析进行验证。

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.