Immune checkpoint inhibitor-induced cardiotoxicity: from immune mechanisms to clinical surveillance and targeted therapies

Figure 1. Proposed immunophysiologic mechanism of ICI targets in cardiomyocytes. This schematic illustrates native role of the many immune checkpoint inhibitor (ICI) targets in the cardiomyocytes and the subsequent effects by which ICI therapy dysregulates the native cardioprotective roles. The PD-1/PD-L1 Axis provides a cardioprotective function in mediating cardiac remodeling via the NF-κB and CD47/SHP2/SIRPα/SYK/FcγR pathway; reduction of the pro-inflammatory cytokine IFN-γ; immune regulation via LAG-3, PD-L1/B7-H1, and PD-L2/B7-DC; and regulation of B-cell tolerance. The CLTA-4 Axis provides cardioprotective effects by mediating T-cell tolerance through the Foxp3+ Treg while also modulating the cytotoxicity of CD8+ T-cells. Upon immune dysregulation by the aforementioned mechanisms, the immune response is susceptible to be exacerbated by other mechanisms like complement activation and molecular mimicry which furthers adverse cardiac remodeling/fibrosis as well as aberrant immune infiltration. [Made using Biorender.com].

Figure 2. Mechanisms of ICI-induced myocarditis. The schematic provides a sequential mechanism by which ICI-therapy results in inflammatory myocardial and pericardial diseases. This begins with CD4+ T-cell recognition of cardiac antigens like troponin and α-Myosin Heavy Chain (α-MyHC). Subsequent dysregulation of the immune system by ICI-therapies involves a decrease in the amount of T-regs, increase in CD8+ T-cell expression, and pro-inflammatory cytokine imbalance as IL-6 increases and TGF-β decreases. Afterwards, the stage is set for numerous pathways of lymphocyte and mononuclear infiltration including CD3+, CD4+, and CD8+ T cell, CD68+ macrophages, and FoxP3+ T cells. In particular, CD8+ T-cell infiltration is further amplified by a positive feedback loop with CCR2+ macrophages with the IL-12b, TNF, and IFN-γ signaling pathway as well as the CXCL9/10 pathway. Moreover, CXCR3 receptor expression and upregulation of the CCL5/CCL4/CCL4L2 pathway can promote direct cardiomyocyte death. CD4+ and CD69+ T-cell infiltration is mediated by upregulation of the ICOS-ICOSL signaling pathway. Lastly, B-cells may mediate autoimmune myocarditis through the secretion of IgG against cardiac myeloid…

Figure 3. Mechanisms of ICI-induced atherosclerosis. This schematic provides an overview of the process of how ICI-therapies promote atherosclerotic plaque development and increase Atherosclerotic Cardiovascular Disease (ASCVD) risk for myocardial infarction and ischemic stroke. First, endothelial dysfunction, the initiation of atherosclerosis, is exacerbated by ICI-induced promotion of leukocyte infiltration through induction of intercellular adhesion molecule-1(ICAM-1) and inducible nitric oxide synthase (iNOS) upregulation. Secondly, the a pro-inflammatory, atherogenic environment is created by an increase in T-cell to macrophage ratio; release of inflammatory mediators like IL-1β, IL-6, TNF-α, and IFN-γ; and polarization to pro-inflammatory M1 macrophages with upregulation of C-X-C Motif Chemokine Ligand 9 (CXCL9). Lastly, vulnerability to plaque rupture is intensified by ICI-therapy dysregulating T-regs from mediating the fibrous cap formation. [Made using Biorender.com].