Yousif Laura I, Tanja Anniek A, de Boer Rudolf A, Teske Arco J, Meijers Wouter C
Department of Experimental Cardiology, University Medical Center Groningen, Groningen, Netherlands.
Graduate School of Life Science, Utrecht University, Utrecht, Netherlands.
Front Pharmacol. 2022 Oct 3;13:989431. doi: 10.3389/fphar.2022.989431. eCollection 2022.
Immune checkpoint inhibitors (ICI) are monoclonal antibodies which bind to immune checkpoints (IC) and their ligands to prevent inhibition of T-cell activation by tumor cells. Currently, multiple ICI are approved targeting Cytotoxic T-lymphocyte antigen 4 (CTLA-4), Programmed Death Protein 1 (PD-1) and its ligand PD-L1, and Lymphocyte-activation gene 3 (LAG-3). This therapy has provided potent anti-tumor effects and improved prognosis for many cancer patients. However, due to systemic effects, patients can develop immune related adverse events (irAE), including possible life threatening cardiovascular irAE, like atherosclerosis, myocarditis and cardiomyopathy. Inhibition of vascular IC is associated with increased atherosclerotic burden and plaque instability. IC protect against atherosclerosis by inhibiting T-cell activity and cytokine production, promoting regulatory T-cell differentiation and inducing T-cell exhaustion. In addition, PD-L1 on endothelial cells might promote plaque stability by reducing apoptosis and increasing expression of tight junction molecules. In the heart, IC downregulate the immune response to protect against cardiac injury by reducing T-cell activity and migration. Here, inhibition of IC could induce life-threatening T-cell-mediated-myocarditis. One proposed purpose behind lymphocyte infiltration is reaction to cardiac antigens, caused by decreased self-tolerance, and thereby increased autoimmunity because of IC inhibition. In addition, there are several reports of ICI-mediated cardiomyopathy with immunoglobulin G expression on cardiomyocytes, indicating an autoimmune response. IC are mostly known due to their cardiotoxicity. However, t his review compiles current knowledge on mechanisms behind IC function in cardiovascular disease with the aim of providing an overview of possible therapeutic targets in prevention or treatment of cardiovascular irAEs.
免疫检查点抑制剂（ICI）是一类单克隆抗体，可与免疫检查点（IC）及其配体结合，以防止肿瘤细胞对T细胞活化的抑制。目前，多种ICI已获批准，靶向细胞毒性T淋巴细胞抗原4（CTLA-4）、程序性死亡蛋白1（PD-1）及其配体PD-L1以及淋巴细胞激活基因3（LAG-3）。这种疗法已为许多癌症患者带来了强大的抗肿瘤作用并改善了预后。然而，由于其全身性影响，患者可能会出现免疫相关不良事件（irAE），包括可能危及生命的心血管irAE，如动脉粥样硬化、心肌炎和心肌病。抑制血管IC与动脉粥样硬化负担增加和斑块不稳定有关。IC通过抑制T细胞活性和细胞因子产生、促进调节性T细胞分化以及诱导T细胞耗竭来预防动脉粥样硬化。此外，内皮细胞上的PD-L1可能通过减少细胞凋亡和增加紧密连接分子的表达来促进斑块稳定性。在心脏中，IC通过降低T细胞活性和迁移来下调免疫反应，以保护心脏免受损伤。在此，抑制IC可能会诱发危及生命的T细胞介导的心肌炎。淋巴细胞浸润背后的一个推测原因是对心脏抗原的反应，这是由自身耐受性降低引起的，从而由于IC抑制导致自身免疫增加。此外，有几篇关于ICI介导的心肌病的报道，心肌细胞上有免疫球蛋白G表达，表明存在自身免疫反应。IC大多因其心脏毒性而为人所知。然而，本综述汇编了关于IC在心血管疾病中功能机制的当前知识，旨在概述预防或治疗心血管irAE中可能的治疗靶点。
