Immune Checkpoint Therapies and Atherosclerosis: Mechanisms and Clinical Implications: JACC State-of-the-Art Review

Abstract

Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced malignancies in recent years. Numerous reports have detailed the myriad of possible adverse inflammatory effects of immune checkpoint therapies, including within the cardiovascular system. However, these reports have been largely limited to myocarditis. The critical role of inflammation and adaptive immunity in atherosclerosis has been well characterized in preclinical studies, and several emerging clinical studies indicate a potential role of immune checkpoint targeting therapies in the development and exacerbation of atherosclerosis. In this review, we provide an overview of the role of T-cell immunity in atherogenesis and describe the molecular effects and clinical associations of both approved and investigational immune checkpoint therapy on atherosclerosis. We also highlight the role of cholesterol metabolism in oncogenesis and discuss the implications of these associations on future treatment and monitoring of atherosclerotic cardiovascular disease in the oncologic population receiving immune checkpoint therapy.

Keywords: atherosclerosis; cardio-oncology; cardiovascular disease; immunology; inflammation.

Figure 1. T Cell Activation and Effect of Immune Checkpoints.

A. T Cell Activation. Antigen presenting cells (APCs) present antigens via major histocompatibility complex (MHC) molecules that bind to T cell receptors (TCR) on naïve CD4+ and CD8+ T cells. T cell activation requires the binding of costimulatory molecules B7.1(CD80) or B7.2(CD86) on APCs to CD28. Naïve CD8+ T cells are activated into cytotoxic T cells that secrete perforins and granzymes, leading to apoptotic cascades in target cells. The presence of particular cytokines and growth factors in the microenvironment determine naïve CD4+ T cell differentiation. B. Immune Alterations in Cancer and Effect of Immune Checkpoint Inhibitors. Prolonged inflammation in cancer leads to T cell exhaustion that promotes recruitment of T_reg cells and increased expression of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 receptor (PD-1) on T cells. Programmed cell death protein 1 receptor ligand (PD-L1) on tumor cells binds to PD-1 to decrease the production of inflammatory cytokines. Immune checkpoint inhibitors enhance tumor cell killing by targeting PD-1, PD-L1 and CTLA-4 to restore T cell activation and inflammatory cytokine production. Created with BioRender.

Figure 2. Atherogenesis and Effects of T Cell Activation.

Damaged endothelial cells express platelet endothelial cell adhesion molecules (PECAM), intracellular adhesion molecules (ICAM), vascular cell adhesion protein (VCAM) and selectins that recruit monocytes to the subendothelium. Monocytes are activated into macrophages that consume oxidized low density lipoproteins (ox-LDL) and produce inflammatory cytokines, leading to foam cell and necrotic core formation. T cells are recruited to the subendothelium and activated by APCs. Activation of T helper 1 (T_h1) cells leads to tumor necrosis factor alpha (TNF-α) secretion that promotes monocyte recruitment and endothelial damage, and interferon gamma (IFN-γ) secretion that promotes macrophage activation. T cell activation decreases the function of regulatory T cells (T_reg) that normally decreases T cell and monocyte recruitment via transforming growth factor-beta (TGF-β) secretion and reduces T_h1 differentiation via interleukin-10 (IL-10) secretion. T cell activation is enhanced by immune checkpoint altering antibodies. Created with BioRender.

Central Illustration:. Summary of Immune Checkpoint Alterations and their Effects on Atherogenesis.

CTLA-4 and PD-1/PDL-1 blockade are well-studied examples of co-inhibitory molecule blockade that worsen atherosclerosis. CD40/CD40L agonism and GITR agonism are examples of co-stimulatory molecule agonism that worsen atherosclerosis. CD-47 blockade restores efferocytosis and may be atheroprotective. APC indicates antigen presenting cell; MHC, major histocompatibility complex, TCR, T cell receptor, CTLA4, cytotoxic T-lymphocyte associated protein 4; PD-1, Programmed cell death protein 1 receptor; PD-L1, Programmed cell death protein 1 receptor ligand; SIRP-α, signal-regulatory protein alpha; CD, cluster of differentiation; GITR, glucocorticoid-induced tumor necrosis factor family-related protein; GITRL, glucocorticoid-induced tumor necrosis factor family-related protein ligand; Treg, regulatory T cell; VCAM, vascular cell adhesion molecule; and MMP, matrix metalloproteinase. Created with BioRender.