Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?

Abstract

Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the formation of plaques containing lipid, connective tissue and immune cells in the intima of large and medium-sized arteries. Over the past three decades, a substantial reduction in cardiovascular mortality has been achieved largely through LDL-cholesterol-lowering regimes and therapies targeting other traditional risk factors for cardiovascular disease, such as hypertension, smoking, diabetes mellitus and obesity. However, the overall benefits of targeting these risk factors have stagnated, and a huge global burden of cardiovascular disease remains. The indispensable role of immunological components in the establishment and chronicity of atherosclerosis has come to the forefront as a clinical target, with proof-of-principle studies demonstrating the benefit and challenges of targeting inflammation and the immune system in cardiovascular disease. In this Review, we provide an overview of the role of the immune system in atherosclerosis by discussing findings from preclinical research and clinical trials. We also identify important challenges that need to be addressed to advance the field and for successful clinical translation, including patient selection, identification of responders and non-responders to immunotherapies, implementation of patient immunophenotyping and potential surrogate end points for vascular inflammation. Finally, we provide strategic guidance for the translation of novel targets of immunotherapy into improvements in patient outcomes.

Fig. 1. History of research into the role of inflammation in atherosclerosis.

The timeline shows the main milestones in the past four decades of research into the role of inflammation in atherosclerosis. In the 1980s, the introduction of immunohistochemical techniques to study atherosclerotic plaques provided evidence of HLA-DR expression in human atherosclerotic plaques, followed by identification of monocytes, macrophages and T cells in the plaque^,,–. In the 1990s, studies showed the presence of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), in atherosclerotic plaques^–, and the association between high plasma C-reactive protein (CRP) levels and coronary artery disease (CAD)^,. During this decade, the first mouse models of hypercholesterolaemia with an inflammatory gene knockout were developed^,, and titres of antibodies against oxidized LDL (oxLDL) in the serum were shown to predict cardiovascular disease outcomes. In the 2000s, studies demonstrated the association between increased levels of inflammatory markers and increased risk of cardiovascular events^,. An increased risk of cardiovascular disease was shown in patients with inflammatory diseases^–, and several studies demonstrated the association between elevated levels of CRP, IL-6 and TNF in the plasma and worse clinical outcomes in patients with cardiovascular disease^,,,. This finding led to the introduction of inflammation as a therapeutic target in cardiovascular disease. In the late 2010s, studies showed that immune checkpoint inhibitor treatment increased the risk of cardiovascular disease in patients with cancer^,. In the past decade, clinical trials investigated whether targeting inflammation in cardiovascular disease is beneficial^,,. Numerous studies also demonstrated the involvement of the bone marrow in atherosclerosis^,, and performed single-cell analysis of plaque immune cells^,. Preclinical discoveries are shown in blue boxes and clinical discoveries in red boxes. MI, myocardial infarction; VSMC, vascular smooth muscle cell.

Fig. 2. Inflammation in atherosclerosis.

In medium and large arteries, haemodynamic forces create areas of low shear stress that are often predictors of atherosclerotic plaque location. As the atherosclerotic plaque begins to form, circulating apolipoprotein B (ApoB)-containing lipoproteins (ApoB-LP) and ApoB peptides enter the subendothelial space, where they can be modified and recognized by innate immune cells as danger signals. These danger signals activate Toll-like receptor (TLR) signalling and the inflammasome in innate immune cells, eliciting responses that drive inflammation, including production and secretion of cytokines, release of neutrophil extracellular traps (NETs), upregulation of co-stimulatory molecules and promotion of monocyte recruitment to the plaque. Macrophages derived from monocyte differentiation, local proliferation or from transdifferentiation of vascular smooth muscle cells (VSMCs) take up lipoproteins present in the plaque and become lipid-laden foam cells that lay the foundation for the formation of the plaque necrotic core. At the immune synapse, antigen-presenting cells (APCs), including macrophages, dendritic cells and B cells, present lipid antigens to invariant natural killer T (iNKT) cells and peptide antigens to T cells, the latter engaging adaptive T cell and B cell responses. Antigen presentation occurs in the plaque and in secondary lymph organs, such as the lymph node. Together, all these processes contribute to endothelial dysfunction, leading to further aggravation of inflammation through continued monocyte recruitment, increased uptake of lipoproteins adding to the plaque lipid burden, VSMC activation and proliferation, and fibroblast migration contributing to fibrous cap formation. ECM, extracellular matrix; IFN, interferon; MHC, major histocompatibility complex; ROS, reactive oxygen species; TCR, T cell receptor; T_H1, T helper 1; TNF, tumour necrosis factor; T_reg cell, regulatory T cell.

Fig. 3. Targeting the immune system in atherosclerosis.

a–d | Immunotherapies for the treatment of atherosclerosis that showed benefit (green), no benefit (red) or potential benefit (yellow) in reducing inflammation or cardiovascular events in clinical trials or currently being tested in ongoing clinical trials (blue) are shown. Therapeutics targeting innate immunity include IL-1 inhibitors, IL-6 inhibitors, tumour necrosis factor (TNF) blockers and p38 inhibitors (panel a). Therapeutics targeting adaptive immunity include local proliferation inhibitors in drug-eluting stents and low-dose IL-2 targeting regulatory T (T_reg) cells (panel b). Therapeutics targeting lipoproteins to reduce inflammation include antibodies against oxidized LDL (oxLDL), lipoprotein-associated phospholipase A2 (Lp-PLA₂), secretory phospholipase A2 (sPLA₂) and lectin-like oxidized LDL receptor 1 (LOX1) (panel c). Therapeutics with broad immunosuppressive effects include colchicine, low-dose methotrexate, glucocorticoids and hydroxychloroquine (panel d). See Tables 1,2 and 3 and Supplementary Table 1 for further details. e–g | Overview of therapeutics in preclinical development targeting innate immunity (panel e), co-stimulation pathways (panel f) and B cell and T cell regulation (panel g). APC, antigen-presenting cell; ApoB, apolipoprotein B; BAFF, B cell activating factor; BCMA, B cell maturation antigen; BTLA, B and T lymphocyte attenuator; CCR, C-C chemokine receptor; CD30L, CD30 ligand; CD40L, CD40 ligand; CTLA4, cytotoxic T lymphocyte antigen 4; CVD, cardiovascular disease; GLUT1, glucose transporter 1; HDAC, histone deacetylase; HSPC, haematopoietic stem and progenitor cell; IRF5, interferon regulatory factor 5; OX40L, OX40 ligand; PPARγ, peroxisome proliferator-activated receptor-γ; siRNA, small interfering RNA; SPM, specialized pro-resolving mediators; TLR, Toll-like receptor; TRAF6, tumour necrosis factor receptor-associated factor 6.