Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA-34a/Kruppel-like factor 4 signaling

Abstract

Cancer immunotherapy has become a well-established treatment option for some cancers; however, its use is hampered by its cardiovascular adverse effects. Immune checkpoint inhibitors (ICIs)-related cardiac toxicity took place in kinds of different forms, such as myocarditis, acute coronary syndrome, and pericardial disease, with high mortality rates. This study aimed to investigate the roles of programmed death-1 (PD-1) inhibitor, one of widespread used ICIs, in the development of murine cardiac injury. PD-1 inhibitor is known to transduce immunoregulatory signals that modulate macrophages polarization to attack tumor cells. Hence, this study explored whether the cardiovascular adverse effects of PD-1 inhibitor were related to macrophage polarization. MicroRNA-34a (miR-34a), which appears to regulate the polarization of cultured macrophages to induce inflammation, is examined in cardiac injury and macrophage polarization induced by the PD-1 inhibitor. As a target of miR-34a, Krüppel-like factor 4 (KLF4) acted as an anti-inflammation effector to take cardiac protective effect. Further, it investigated whether modulating the miR-34a/KLF4-signaling pathway could influence macrophage polarization. The PD-1 inhibitor markedly induced M1 phenotype macrophage polarization with impaired cardiac function, whereas miR-34a inhibitor transfection treatment reversed M1 polarization and cardiac injury in vivo. In vitro, PD-1 inhibitor-induced M1 polarization was accompanied by an increase in the expression of miR-34a but a decrease in the expression of KLF4. TargetScan and luciferase assay showed that miR-34a targeted the KLF4 3′-untranslated region. Either miR-34a inhibition or KLF4 overexpression could abolish M1 polarization induced by the PD-1 inhibitor. The findings strongly suggested that the PD-1 inhibitor exerted its effect in promoting M1 polarization and cardiac injury by modulating the miR-34a/KLF4-signaling pathway and inducing myocardial inflammation. These findings might help us to understand the pathogenesis of cardiac injury during immunotherapy, and provide new targets in ameliorating cardiac injury in patients with cancer receiving PD-1 inhibitor treatment.

Immune Checkpoint Inhibitors: Cardiotoxicity in Pre-clinical Models and Clinical Studies

“…Similarly, in a mouse model, PD-1 blockade significantly increased cytotoxic T-cells in the myocardium (28). In another mouse study, PD-1 antibodies influenced macrophage infiltration and subsequent M1 polarization (29). However, translational discrepancies between mouse models and the clinical presentation of IRAEs hinder mechanistic research and possible therapeutic options.…”

Comparative Transcriptomics of Immune Checkpoint Inhibitor Myocarditis Identifies Guanylate Binding Protein 5 and 6 Dysregulation

“…In another study, a combination of coxsackievirus B3 infection and PD-1/PD-L1 inhibitors induced acute myocarditis [20]. Another two studies in which C57/Bl6 mice were treated with PD-1 inhibitors [21] or CTLA-4 inhibitors [22] describe a deterioration in left ventricular function in response to the blockage of the immune checkpoints.…”

MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic

“…Clinical use of programmed cell death-1 (PD-1) checkpoint inhibitors is frequently associated with cardiac toxicity due to proinflammatory reactions. Interestingly, inhibition of miR-34a has been shown to suppress M1 macrophage polarization via targeting KLF4, a critical regulator of macrophage M1/M2 polarization, and improve the cardiac functions impaired by PD-1 inhibitor ( Xia et al, 2020 ).…”