Immune checkpoint inhibitors and accelerated coronary atherosclerosis

项目概要/摘要 免疫检查点抑制剂（ICI）代表了癌症护理的范式转变，利用免疫系统 to target目标cancer癌cells细胞.在动物和基础研究中，这些通路（PD-1、PD-L1和CTLA-4）也很关键 在动物研究中，动脉粥样硬化的负调节因子和PD-1、PD-L1和CTLA-4的阻断激活T细胞 细胞导致T细胞浸润和动脉粥样硬化增加。我们提供回顾性临床和成像 在一项前瞻性研究中，有数据支持我们的假设，即ICI会增加冠状动脉粥样硬化。我们将 通过进行一项前瞻性观察性冠状动脉CTA研究来检验这一假设，其中135名患者（最初 入组300例患有黑色素瘤的患者，有和没有BRAF突变（2：1的比例，ICI/BRAF），将接受一系列 基线、12个月（亚组）和2年时的冠脉CTA。BRAF突变黑色素瘤患者 接受BRAF抑制剂，并将作为对照组，而BRAF阴性患者用ICI治疗。 在目标2中，基于先前的工作，我们将测试预先指定的合理生物学因素是否与已建立的 与斑块进展相关（例如PD-1、PD-L1、sCD 163、sCD 14、MCP-1、IL-6、IL-1b）介导了 加速动脉粥样硬化和脑缺血例如，较低的PD-1和PD-L1水平与较高的 冠状动脉粥样硬化斑块，其中PD-1和PD-L1均抑制斑块中T细胞驱动的炎症 和斑块进展。在目标3中，我们将使用单细胞RNA进行无偏探索性分析， 系统地破译免疫细胞的技术。在未接受ICI的患者中，特异性T 细胞亚群与动脉粥样硬化有关，在初步数据中，我们显示了特异性T细胞的激活 (CD8+）与其他ICI毒性。ICI的使用已经增加并继续快速扩展。据估计 目前有36%的癌症患者有资格接受ICI， ICIs是非凡的。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，并提供有关机制的见解。

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.