Elucidating type 1 conventional dendritic cell-dependent anti-tumour immune responses in brain metastases

阐明脑转移瘤中 1 型传统树突状细胞依赖性抗肿瘤免疫反应

• 批准号: MR/Y013328/1
• 负责人: Mihaela Lorger
• 金额: $ 93.93万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013328%2F1
• 关键词: Elucidating; type; conventional; dendritic; cell

Melanoma is the most aggressive form of skin cancer. Once melanoma has spread throughout the body, it is known as metastatic melanoma. At this stage melanoma becomes very difficult to treat and the standard treatment is effective only in a very small proportion of patients. In recent years new drugs have been approved for the treatment of metastatic melanoma. These drugs inhibit the molecules called PD-1 and CTLA-4 that are present on a subpopulation of white blood cells called T lymphocytes. Inhibition of PD-1 and CTLA-4 helps the immune system to attack the cancer. Although these drugs significantly extend lives of melanoma patients, complete responses upon combined inhibition of PD-1 and CTLA-4 are seen only in 11.5 % of the patients. It is therefore important to gain a better understanding of how these drugs work in order to be able to develop approaches that further improve their efficacy.Notably, the immune system works in different ways within different organs in the body. It is therefore important to understand how the drugs targeting PD-1 and CTLA-4 work within the organs to which melanoma most commonly spreads. Our goal is to understand how the efficacy of PD-1 and CTLA-4 blockade could be improved in the brain, to which cancer spreads in up to 60% of metastatic melanoma patients. The resulting tumours are called brain metastases (BrM) and they are particularly difficult to treat. In comparison to the melanoma in general, we know very little about BrM; this is because - despite their high incidence - patients with BrM used to be frequently excluded from clinical trials and BrM are experimentally strongly understudied. Notably, brain has a very distinct cellular composition, with the blood-brain barrier hindering access of drugs and molecules, and it lacks lymphatic vessels that play an important role in initiation of immune responses. Ignoring these specifics of the brain poses a danger that - despite a progress in the treatment of melanoma in other parts of the body - treatment of BrM once again lacks behind and BrM become a limiting factor in patient survival. It is therefore critical to identify the mechanisms involved in the action of drugs targeting PD-1 and CTLA-4 in BrM in a timely manner.There are only very few studies investigating how the drugs targeting PD-1 and CTLA-4 work in BrM. To study this, we previously established an in vivo model of melanoma BrM and demonstrated that a combined targeting of CTLA-4 and PD-1 significantly inhibits growth of BrM and prolongs the survival. This was mainly mediated by a subpopulation of T lymphocytes called Cytotoxic T lymphocytes (CTLs). For T lymphocytes to develop into CTLs that can kill cancer cells, they need help from another population of white blood cells called dendritic cells (DCs). DCs take up molecules derived from cancer cells and present these to T lymphocytes, which induces their activation into CTLs. There are different types of DCs. Our studies demonstrated that type 1 conventional dendritic cells (cDC1s) are required for the control of tumour growth in BrM. We therefore aim to determine how exactly are cDC1s involved in the control of BrM growth following therapy targeting PD-1 and CTLA-4, and how cDC1s in the brain differ from those outside the brain.Understanding how cDC1s support immune responses against BrM will enable the development of strategies that can enhance the ability of cDC1s to support CTLs in their attack against cancer and are therefore expected to potentiate the efficacy of therapy targeting PD-1 and CTLA-4. At least part of the newly gained knowledge is expected to be applicable to melanoma at sites other than the brain. Thus, the knowledge emerging from the proposed research has a potential to contribute towards improved outcomes of patients with BrM and those with metastatic melanoma in general, as well as other cancers.

黑色素瘤是皮肤癌最具侵略性的形式。一旦黑色素瘤遍布整个体内，它就被称为转移性黑色素瘤。在此阶段，黑色素瘤变得非常难以治疗，并且标准治疗仅在很小比例的患者中有效。近年来，新药已被批准用于治疗转移性黑色素瘤。这些药物抑制了在称为T淋巴细胞的白细胞亚群中存在的称为PD-1和CTLA-4的分子。 PD-1和CTLA-4的抑制有助于免疫系统攻击癌症。尽管这些药物显着延长了黑色素瘤患者的生命，但仅在11.5％的患者中只能看到PD-1和CTLA-4联合抑制后的完全反应。因此，重要的是要更好地了解这些药物如何起作用，以便能够开发出进一步提高其有效性的方法。尤其是，免疫系统在体内不同的器官中以不同的方式工作。因此，重要的是要了解靶向PD-1和CTLA-4的药物如何在黑色素瘤最常传播的器官中起作用。我们的目标是了解PD-1和CTLA-4封锁的疗效如何在大脑中改善，癌症在多达60％的转移性黑色素瘤患者中传播。所得的肿瘤称为脑转移（BRM），它们特别难以治疗。与一般黑色素瘤相比，我们对BRM一无所知。这是因为 - 尽管发生了很高的发病率，但BRM患者曾经经常被临床试验排除，而BRM经常被实验深入研究。值得注意的是，大脑具有非常不同的细胞组成，具有阻碍药物和分子的血脑屏障障碍，并且缺乏在免疫反应开始中起重要作用的淋巴管。忽略这些大脑的这些细节构成了一种危险，尽管在身体其他部位的黑色素瘤治疗方面取得了进展，但BRM的治疗再次缺乏后面，而BRM成为患者生存的限制因素。因此，至关重要的是，及时确定针对PD-1和CTLA-4的药物所涉及的机制。只有很少有研究研究靶向PD-1和CTLA-4的药物如何在BRM中工作。为了研究这一点，我们先前建立了一个黑色素瘤BRM的体内模型，并证明CTLA-4和PD-1的靶向靶向显着抑制了BRM的生长并延长了生存率。这主要是由称为细胞毒性T淋巴细胞（CTL）的T淋巴细胞亚群介导的。为了使T淋巴细胞发展成可以杀死癌细胞的CTL，需要从另一个称为树突状细胞（DCS）的白细胞群中的帮助。 DC占据了源自癌细胞的分子，并将其呈现给T淋巴细胞，从而诱导它们的激活成CTL。有不同类型的DC。我们的研究表明，控制BRM肿瘤生长需要1型常规树突状细胞（CDC1）。因此，我们旨在确定针对PD-1和CTLA-4的治疗后，CDC1与CDC1的控制如何完全涉及控制BRM生长，以及大脑中的CDC1与大脑外部的CDC1如何不同。理解CDC1如何支持BRM的免疫反应将启用免疫反应制定策略可以增强CDC1在对癌症攻击中支持CTL的能力，因此有望增强针对PD-1和CTLA-4的治疗的功效。预计至少有一部分新获得的知识将适用于大脑以外的其他部位的黑色素瘤。因此，拟议研究中浮现出的知识有可能为改善BRM患者以及整个转移性黑色素瘤以及其他癌症患者的预后做出贡献。