The regulation of tumour cell cytolysis by cancer associated fibroblasts

癌症相关成纤维细胞对肿瘤细胞溶解的调节

• 批准号: 2749730
• 金额: --
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Studentship
• 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: https://gtr.ukri.org/projects?ref=studentship-2749730
• 关键词: regulation; tumour; cell; cytolysis; cancer

Context of researchThe tumour microenvironment includes a diverse number of cell types including immune cells, fibroblasts, and endothelial cells. Investigating the association between cytotoxic T lymphocytes (CTLs) and cancer associated fibroblasts (CAFs) could provide insights into the crosstalk and impact of CTLs and CAFs on tumour progression and also opens new areas for therapeutic intervention. CTLs are immune cells that can kill cancer cells. However, recruitment and activation of CTLs is often suppressed in the tumour. CAFs shape the extracellular matrix and can secrete immune-modulatory as well as tumour promoting/restricting cytokines. Further research is needed to better understand the impact of CAFs on CTLs ability to kill tumour cells. Aims and ObjectivesThe project has 2 major aims. Aim 1 focuses on CAFs and asks how different CAFs interact with tumour cells and immune cells, particularly CTLs. We will characterise CAFs (particularly those associated with breast and colorectal cancer) and investigate their ability to support cancer cell proliferation in 2D and 3D co-culture assays. In parallel, we will assess the immune-suppressive function of CAFs, e.g. the impact of the CAF secretome on CTL proliferation, migration and the cytolytic activity of CTLs. The objective is to then combine CAFs, tumour cells and CTLs into a 3D co-culture model. Aim 2 will focus on the activity of novel bispecific T-cell engagers (BiTEs). The BiTEs will bind both T-cells and receptors such as EGFR or HER2 on tumour cells. We will compare CTL-induced killing of tumour cells by endogenous CTLs and BiTE-directed CTLs. The project will further address whether expression of varying levels of EGFR/HER2 on cancer cells has an impact on the activity profile of the BiTEs. To better understand the role of CAFs on therapy response, we will bring aim 1 and 2 together, and investigate the impact of CAFs on CTL and BiTE-directed CTL induced tumour cell cytolysis in the co-culture system. potential application and benefitsCAFs are implicit in many solid tumours and are therefore an attractive target for cancer therapy. A clear understanding of their function and interaction with other cells would allow for better drug design. Furthermore, studying the mechanism of function of a bispecific molecule within the CAF/CTL environment will aid development of future immunotherapies. Relevance to the research councilThis is PhD project is within the GW4-BioMed-2 DTP. It is within the "Infection, immunity, antimicrobial resistance and repair" theme. The proposed project is aligned with the MRC's strategy to invest in research addressing biological complexity in real life and is relevant to the MRC's health focus themes of 'precision medicine' and 'advanced therapies'. Furthermore, it addresses core skill areas outlined by the GW4-BioMed-2 DTP including quantitative and interdisciplinary skills.

肿瘤微环境包括多种细胞类型，包括免疫细胞、成纤维细胞和内皮细胞。研究细胞毒性T淋巴细胞（CTL）和癌症相关成纤维细胞（CAF）之间的关联可以深入了解CTL和CAF对肿瘤进展的串扰和影响，也为治疗干预开辟了新的领域。CTL是可以杀死癌细胞的免疫细胞。然而，CTL的募集和激活通常在肿瘤中受到抑制。CAF塑造细胞外基质，并可以分泌免疫调节以及肿瘤促进/限制细胞因子。需要进一步的研究来更好地了解CAF对CTL杀死肿瘤细胞能力的影响。目的和目标该项目有两个主要目标。目的1关注CAFs，并询问不同的CAFs如何与肿瘤细胞和免疫细胞，特别是CTL相互作用。我们将研究CAFs（特别是与乳腺癌和结直肠癌相关的CAFs），并研究它们在2D和3D共培养试验中支持癌细胞增殖的能力。同时，我们将评估CAF的免疫抑制功能，例如CAF分泌组对CTL增殖、迁移和CTL的细胞溶解活性的影响。目的是然后将联合收割机CAF、肿瘤细胞和CTL组合成3D共培养模型。目标2将集中于新型双特异性T细胞增殖剂（BiTE）的活性。BiTE将结合T细胞和肿瘤细胞上的受体如EGFR或HER 2。我们将通过内源性CTL和BiTE定向CTL比较CTL诱导的肿瘤细胞杀伤。该项目将进一步研究癌细胞上不同水平的EGFR/HER 2表达是否对BiTE的活性特征产生影响。为了更好地理解CAF对治疗反应的作用，我们将目标1和2结合在一起，并研究CAF对共培养系统中CTL和BiTE定向的CTL诱导的肿瘤细胞溶解的影响。潜在的应用和益处CAF隐含在许多实体瘤中，因此是癌症治疗的有吸引力的靶点。清楚地了解它们的功能以及与其他细胞的相互作用将有助于更好的药物设计。此外，研究CAF/CTL环境中双特异性分子的功能机制将有助于未来免疫疗法的开发。与研究委员会的相关性这是一个博士项目，属于GW 4-BioMed-2 DTP。它是在“感染，免疫力，抗菌素耐药性和修复”的主题。拟议的项目与MRC的战略相一致，即投资于解决真实的生活中生物复杂性的研究，并与MRC的“精准医学”和“先进疗法”的健康重点主题有关。此外，它还涉及GW 4-BioMed-2 DTP概述的核心技能领域，包括定量和跨学科技能。