Immune checkpoint inhibitors associated cardiovascular immune-related adverse events

Abstract

Immune checkpoint inhibitors (ICIs) are specialized monoclonal antibodies (mAbs) that target immune checkpoints and their ligands, counteracting cancer cell-induced T-cell suppression. Approved ICIs like cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene-3 (LAG-3) have improved cancer patient outcomes by enhancing anti-tumor responses. However, some patients are unresponsive, and others experience immune-related adverse events (irAEs), affecting organs like the lung, liver, intestine, skin and now the cardiovascular system. These cardiac irAEs include conditions like myocarditis, atherosclerosis, pericarditis, arrhythmias, and cardiomyopathy. Ongoing clinical trials investigate promising alternative co-inhibitory receptor targets, including T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). This review delves into the mechanisms of approved ICIs (CTLA-4, PD-1, PD-L1, and LAG-3) and upcoming options like Tim-3 and TIGIT. It explores the use of ICIs in cancer treatment, supported by both preclinical and clinical data. Additionally, it examines the mechanisms behind cardiac toxic irAEs, focusing on ICI-associated myocarditis and atherosclerosis. These insights are vital as ICIs continue to revolutionize cancer therapy, offering hope to patients, while also necessitating careful monitoring and management of potential side effects, including emerging cardiac complications.

Keywords: CTLA-4; LAG-3; PD-1; TIGIT; TIM-3; atherosclerosis; immune checkpoint inhibitors; myocarditis.

Figure 1

Pathogenic mechanisms of immune checkpoint inhibitors associated myocarditis. Autoreactive T cells, which recognize cardiac myosin heavy chain, main autoantigen in the heart, play a crucial role in the onset of ICI-myocarditis. These autoreactive T cells may be present in the heart in a naïve state due to impaired thymic selection, expressing elevated levels of IC as a peripheral tolerance mechanism to prevent their activation. In a mouse model, ICI treatment seems to directly activate these autoreactive T cells by obstructing the inhibitory IC pathway, specifically targeting the heart. Recent reports have indicated that anti-CTLA-4 and anti-PD-1/PD-L1 treatments result in the clonal expansion of T cells specific to cardiac myosin, observed in peripheral blood mononuclear cells of patients with ICI-associated myocarditis, indicating their pathogenic role in clinical scenarios. Anti-CTLA-4 is associated with the promotion of Th17-mediated autoimmunity in EAM, while anti-PD-1/PD-L1 is linked to excessive production of T cell derived cytokines and cytotoxic molecules like IFN-γ, perforin, and granzyme B, ultimately contributing to myocarditis development. Notably, anti-LAG-3 has only been associated with ICI-myocarditis when combined with anti-PD-1. CTLA-4, cytotoxic T-lymphocyte antigen-4; EAM, experimental autoimmune myocarditis; IC, immune checkpoint; ICI, immune checkpoint inhibitor; IFN-γ, interferon-γ; LAG-3, lymphocyte activation gene-3; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1, TCR, T-cell receptor; Th17, IL-17-producing T cell (type 17 helper T cell); TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain; Tim-3, T cell immunoglobulin and mucin domain-containing protein 3; TNF, tumor necrosis factor; Treg, regulatory T lymphocytes.

Figure 2

Underlying mechanisms of atherosclerosis linked to immune checkpoint inhibitors. ICI-associated atherosclerosis encompasses an intricate process of plaque formation within arterial walls, commencing with the retention of LDL-cholesterol that triggers inflammation and recruit monocytes into artery walls. These monocytes evolve into cholesterol-laden macrophages, eventually transforming into foam cells, creating a central necrotic area within the plaque. Persistent lipoprotein uptake and macrophage proliferation contribute to plaque enlargement, attracting immune cells, particularly T cells, to the plaque’s periphery. Th1 cells release IFN-γ and TNF, promoting macrophage activation and destabilizing the plaque, potentially leading to heart attacks or strokes. ICIs disrupt this process by activating T cells, producing proinflammatory cytokines like TNF and IFN-γ. These cytokines induce detrimental effects such as immune cell recruitment, smooth muscle cell proliferation, collagen deposition, and macrophage activation, triggering further proinflammatory cytokine release syndrome. This results in increased LDL phagocytosis and foam cell formation, ultimately causing structural changes within the plaque, including the formation of a necrotic core, rendering the plaque more unstable. Anti-CTLA-4, PD-1/PD-L1, and Tim-3 have been demonstrated to be pro-atherogenic, fostering the proliferation of inflammatory immune cells while suppressing the development of Treg and regulatory B cells. CTLA-4, cytotoxic T-lymphocyte antigen-4; IC, immune checkpoint; ICI, immune checkpoint inhibitor; IFN-γ, interferon-γ; IL, interleukin; LAG-3, lymphocyte activation gene-3; LDL, low-density lipoprotein; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1, TCR, T-cell receptor; Th1, type 1 helper T cell; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain; Tim-3, T cell immunoglobulin and mucin domain-containing protein 3; TNF, tumor necrosis factor; Treg, regulatory T lymphocytes.