Targeting cytokines and immune checkpoints in atherosclerosis with monoclonal antibodies
Graphical abstract
Introduction
In the late 19th century, the German pathologist Rudolph Virchow hypothesized that inflammation was of primary importance in atherosclerosis. Almost 100 years later, Russel Ross theorized the interactions among endothelial cells, monocytes, and T cells as players that can induce and promote inflammation and atherogenesis [1]. For decades, the pieces of evidence supporting the inflammatory theory of atherosclerosis were indirect. To date, experimental studies have precisely deciphered the role of the many facets of this low-grade chronic inflammation. However, real-life clinical data supporting this theory are only recent. First, it was backed by the observation of an increased risk of cardiovascular events following an infectious episode [2] and observations reporting a higher cardiovascular risk in patients with autoimmune (rheumatoid arthritis) or dysimmune pro-inflammatory disorders (psoriasis, ankylosing spondylitis, or Crohn's disease) [3,4]. Indeed, large register-based studies reported that patients with psoriasis have a significantly higher risk of MI [5] and stroke [3], compared to control matched individuals with conventional cardiovascular risk factors. Rheumatoid arthritis patients, but also type I diabetes patients have an increased risk of cardiovascular disease (CVD) morbidity and premature mortality [6,7], and CVD risk seems to correlate with the activity of the underlying inflammatory disease [8].
In the early 2000s, the widespread use of anti-cytokine monoclonal antibody has provided relevant proofs for a pathophysiological relationship between inflammation and cardiovascular diseases (Fig. 1). In 2017, the CANTOS trial investigating the anti-IL-1β monoclonal antibody (Canakinumab) in patients with previous myocardial infarction (MI) and a high-sensitivity C-reactive protein (hsCRP) level > two mg/L was the first clinical study to prove that reducing inflammation without lowering lipid levels may reduce the risk of major adverse cardiovascular events (MACE) [9].
This review highlights the clinical studies in which immunotherapeutics, especially drugs targeting cytokines (Table 1) and costimulatory molecules (Table 2), have provided evidence to affect cardiovascular athero-thrombotic events.
Section snippets
TNFα blockade
TNFα is a critical host defense molecule that is conserved through evolution and the first cytokine released in the plasma within minutes after injury. Experimental studies in mice demonstrated TNFα′s implication in atherogenesis. Indeed, in Apoe−/− mice, the genetic deficiency in TNFα reduces ICAM-1, VCAM-1, MCP-1 in the vascular wall, and LDL uptake by macrophages, thereby limiting atherosclerosis progression [10].. In 1990, Barath first identified that human atherosclerotic plaques contain
Targeting costimulatory and co-inhibitory immune checkpoints
Costimulatory and co-inhibitory molecules, the largest classes within the immune checkpoint family, are master regulators of the immune response. In a classic view, costimulatory molecules are known as ‘signal 2': following recognition of an antigen by the T cell receptor, co-stimulation is required to activate (and in some cases dampen) T cell proliferation and activation, whereas co-inhibitory molecules counteract these responses [98]. Nowadays, we know that immune checkpoints not only
Conclusion
In recent years it has become clear that besides lipid-lowering, targeting inflammation is a successful strategy to combat CVD in patients. The CANTOS trial has provided the proof-of-principle that targeting inflammation in CVD is feasible and successful and has paved the way for implementing immunotherapy for CVD. As the CANTOS, and later on the COLCOT and LoDoCo2 trials have shown, the IL1β-inflammasome pathway has been shown to be a prime immunotherapeutic target for CVD. However, as we
CRediT authorship contribution statement
Esther Lutgens: Conceptualization, Writing – original draft, Writing – review & editing, Supervision. Jeremie Joffre: Writing – original draft, tables. Bram van Os: Writing – original draft, figures. Hafid Ait-Oufella: Conceptualization, Writing – original draft, Writing – review & editing, Supervision.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), by the Deutsche Forschungsgemeinschaft (CRC 1123A5 to E.L) and the European Research Council (ERC consolidator grant to E.L).
References (153)
- et al.
Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review
Lancet Infect. Dis.
(2009) - et al.
Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice
Atherosclerosis
(2005) - et al.
Detection and localization of tumor necrosis factor in human atheroma
Am. J. Cardiol.
(1990) - et al.
A polymorphism in the promoter of the tumor necrosis factor-alpha gene (-308) is associated with coronary heart disease in type 2 diabetic patients
Atherosclerosis
(2003) - et al.
Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-alpha inhibitors versus methotrexate
J. Am. Acad. Dermatol.
(2017) - et al.
Leukocytes link local and systemic inflammation in ischemic cardiovascular disease: an expanded "cardiovascular continuum
J. Am. Coll. Cardiol.
(2016) Biologic basis for interleukin-1 in disease
Blood
(1996)Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond
J. Am. Coll. Cardiol.
(2017)- et al.
Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial
Lancet
(2017) - et al.
Low-dose colchicine for secondary prevention of cardiovascular disease
J. Am. Coll. Cardiol.
(2013)
Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis
J. Am. Coll. Cardiol.
Associations of interleukin-5 with plaque development and cardiovascular events
JACC Basic Transl Sci
Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55
Blood
Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall
Atherosclerosis
Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly
Am. J. Med.
Host responses to Candida albicans: Th17 cells and mucosal candidiasis
Microb. Infect.
IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner
J. Biol. Chem.
Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice
Biochem. Biophys. Res. Commun.
Atherosclerosis-an inflammatory disease
N. Engl. J. Med.
Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies
J Am Heart Assoc
Are ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis associated with an increased risk of cardiovascular events? A prospective nationwide population-based cohort study
Arthritis Res. Ther.
Risk of myocardial infarction in patients with psoriasis
J. Am. Med. Assoc.
Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions
Eur. Heart J.
Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies
Ann. Rheum. Dis.
Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis
Ann. Rheum. Dis.
Antiinflammatory therapy with canakinumab for atherosclerotic disease
N. Engl. J. Med.
Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction
Circulation
Polymorphisms in the TNF-alpha and TNF-receptor genes in patients with coronary artery disease
Eur. J. Clin. Invest.
Anti-TNF therapy: past, present and future
Int. Immunol.
Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis
J. Rheumatol.
Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis
Ann. Rheum. Dis.
Carotid intima-media thickness in psoriatic arthritis: differences between tumor necrosis factor-alpha blockers and traditional disease-modifying antirheumatic drugs
Arterioscler. Thromb. Vasc. Biol.
Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study
J. Intern. Med.
Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis
Arch. Dermatol.
European S3-Guidelines on the systemic treatment of psoriasis vulgaris--Update 2015--Short version--EDF in cooperation with EADV and IPC
J. Eur. Acad. Dermatol. Venereol.
Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis
J. Am. Acad. Dermatol.
Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis
Ann. Rheum. Dis.
Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?
Annu. Rev. Immunol.
What effects might anti-TNFalpha treatment be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNFalpha in cardiovascular pathophysiology
Ann. Rheum. Dis.
Low-dose methotrexate for the prevention of atherosclerotic events
N. Engl. J. Med.
Anticytokine agents: targeting interleukin signaling pathways for the treatment of atherothrombosis
Circ. Res.
Innate immunity and the failing heart: the cytokine hypothesis revisited
Circ. Res.
Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy against Congestive Heart Failure (ATTACH) trial
Circulation
NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Nature
Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo - the role of platelet-derived growth factor
J. Clin. Invest.
Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice
Arterioscler. Thromb. Vasc. Biol.
Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases
Nat. Rev. Drug Discov.
Single nucleotide polymorphisms in IL1B and the risk of acute coronary syndrome: a Danish case-cohort study
PloS One
Associations between interleukin-1 gene polymorphisms and coronary heart disease risk: a meta-analysis
PloS One
Use of canakinumab in the cryopyrin-associated periodic syndrome
N. Engl. J. Med.
Cited by (8)
Endothelial-to-mesenchymal transition: advances and controversies
2023, Current Opinion in PhysiologyPrognostic impacts of Lipoxin A4 in patients with acute myocardial infarction: A prospective cohort study
2023, Pharmacological ResearchCitation Excerpt :Most of existing anti-inflammatory medications focus on blocking the initiation of inflammation through certain pathways. For example, colchicine and canakinumab suppress upstream activation of NLRP3 inflammasome and IL-1β, therefore blocking its multifold effects on immune- and non-immune cells for transformation into pro-inflammatory phenotypes [40]. While many autoimmune diseases are mainly caused by the release of certain cytokines or antibodies, the origin of cardiovascular inflammation is usually multiple and closely related to metabolic disorders, for which agents with broader spectrum of anti-inflammatory effects could be more effective [1,4,5,41].
Atherosclerosis With Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: JACC: CardioOncology State-of-the-Art Review
2022, JACC: CardioOncologyCitation Excerpt :Therefore, their inhibition in current oncological immunotherapies may activate T cells in plaques and aggravate atherosclerosis in these patients. While the molecular pathways of ICI-associated atherosclerosis beyond PD-1, PD-L1, and CTLA-4 are incompletely understood, approaches targeting novel co-stimulatory and co-inhibitory immune checkpoints, are currently under investigation (Table 2).58-60 Importantly, not all ICIs that are targeted for cancer are likely to aggravate atherosclerosis, and some may prevent the progression of atherosclerosis.
Dynamical Behaviour of Pro-and Anti-Inflammatory Cytokines during Pathogenesis of Atherosclerosis
2023, Communication in Biomathematical SciencesCD40L modulates CD4<sup>+</sup> T-cell activation through receptor for activated C kinase 1
2023, European Journal of ImmunologyRelationship of Soluble Lectin-Like Low-Density Lipoprotein Receptor-1 (sLOX-1) With Inflammation and Coronary Plaque Progression in Psoriasis
2023, Journal of the American Heart Association
- 1
Co-corresponding authors