Immune checkpoint inhibitors and accelerated coronary atherosclerosis

项目摘要/摘要 免疫检查点抑制剂(ICI)代表了癌症治疗的范式转变，利用了免疫系统 以癌细胞为靶点。在动物和基础研究中，这些通路(PD-1、PD-L1和CTLA-4)也是至关重要的 动脉粥样硬化的负性调节因子和阻断动物实验中PD-1、PD-L1和CTLA-4激活T细胞 导致T细胞浸润和动脉粥样硬化加重。我们提供回顾性的临床和影像检查 在一项前瞻性研究中，数据支持了我们的假设，即ICI将增加冠状动脉粥样硬化。我们会 通过执行前瞻性观察性冠状动脉CTA研究来验证这一假设，135名患者(最初 登记300)患有黑色素瘤，有和没有BRAF突变(2：1比率，ICI/BRAF)，将接受一系列 冠状动脉CTA在基线、12个月(亚组)和2年时。伴有BRAF突变的黑色素瘤患者 接受BRAF抑制剂治疗作为对照组，而BRAF阴性患者接受ICI治疗。 在目标2中，我们将在以前工作的基础上，测试预先指定的看似合理的生物因素是否已建立 斑块进展的相关性(如PD-1、PD-L1、sCD163、sCD14、MCP-1、IL-6、IL-1b)介导 伴有ICI的动脉粥样硬化加速。例如，PD-1和PD-L1水平较低与较高 冠状动脉粥样硬化斑块中PD-1和PD-L1均抑制斑块中T细胞驱动的炎症 和斑块的进展。在目标3中，我们将应用单细胞RNA进行无偏见的探索性分析 系统地破译免疫细胞的技术。在患者身上，而不是在ICI上，特异性T细胞 细胞亚群与动脉粥样硬化有关，在初步数据中，我们显示了特定T细胞的激活 (CD8+)合并其他ICI毒性。ICI的使用已经增加，并继续迅速扩大。据估计， 36%的癌症患者目前有资格接受ICI，以及利用 ICIS非同寻常。因此，迫切需要在临床研究中测试ICI是否会导致 加速冠状动脉粥样硬化，并提供对相关机制的洞察。

Project Summary/Abstract Immune checkpoint inhibitors (ICI’s) represent a paradigm shift in cancer care, leveraging the immune system to target cancer cells. In animal and basic studies, these pathways (PD-1, PD-L1 and CTLA-4) are also critical negative regulators of atherosclerosis and blockade of PD-1, PD-L1 and CTLA-4 in animal studies activates T cells leading to T cell infiltration and increased atherosclerosis. We provide retrospective clinical and imaging data to support our hypothesis that ICI’s will increase coronary atherosclerosis in a prospective study. We will test this hypothesis by performing a prospective observational coronary CTA study, where 135 patients (initially enrolling 300) with melanoma, with and without the BRAF mutation (2:1 ratio, ICI/BRAF), will undergo serial coronary CTA at baseline, 12 months (sub-group) and 2 years. Patients with melanoma with a BRAF mutation receive BRAF inhibitors and will act as the control group, while BRAF negative patients are treated with an ICI. In Aim 2, based on prior work, we will test whether pre-specified plausible biological factors with established associations with plaque progression (e.g. PD-1, PD-L1, sCD163, sCD14, MCP-1, IL-6, IL-1b) mediate the accelerated atherosclerosis with ICI’s. For example, lower PD-1 and PD-L1 levels associate with higher coronary atherosclerotic plaque where both PD-1 and PD-L1 suppress T cell–driven inflammation in plaques and plaque progression. In Aim 3, we will perform unbiased exploratory analyses applying single-cell RNA technologies to systematically decipher the immune cells that contribute. In patients, not on an ICI, specific T cell subsets have been linked to atherosclerosis and, in preliminary data, we show activation of specific T cells (CD8+) with other ICI toxicities. The use of ICI’s has increased and continues to rapidly expand. It is estimated that 36% of cancer patients are currently eligible for an ICI and the number of active clinical trials leveraging ICIs is extraordinary. Therefore, there is an urgent need to test in a clinical study whether ICI’s lead to accelerated coronary atherosclerosis and to provide insight into the mechanisms involved.