Elsevier

Atherosclerosis

Volume 335, October 2021, Pages 98-109
Atherosclerosis

Targeting cytokines and immune checkpoints in atherosclerosis with monoclonal antibodies

https://doi.org/10.1016/j.atherosclerosis.2021.09.024Get rights and content

Highlights

  • Cardiovascular impact of human antibodies validates the role of inflammation identified in experimental atherosclerosis.

  • Monoclonal antibodies targeting IL-1β, TNF-α and IL-6 pathways protect against athero-thrombotic cardiovascular events.

  • Immunotherapeutics blocking co-stimulatory immune checkpoint such as CD80/CD86 and CD40 reduce cardiovascular events.

  • Blocking co-inhibitory immune checkpoint including PD(L)-1 and CTL-4 seems to aggravate cardiovascular events.

Abstract

Over the past fifteen years, treatments using monoclonal antibodies specifically targeting cytokines have been developed to treat chronic inflammatory diseases, including rheumatoid arthritis or psoriasis, both associated with increased cardiovascular risk. The cardiovascular impact of these therapies allows us to validate the clinical relevance of the knowledge acquired from experimental studies about the role of cytokines in atherosclerosis. Several clinical studies have confirmed the protective effects of anti-TNFα and anti-IL-6R monoclonal antibodies against athero-thrombotic cardiovascular risk in patients with chronic inflammatory diseases. Yet, caution is needed since anti-TNFα treatment can aggravate chronic heart failure. More recently, the CANTOS study showed for the first time that an anti-inflammatory treatment using anti-IL-1β monoclonal antibody in coronary artery disease patients significantly reduced cardiovascular events. The effects of IL-23/IL-17 axis blockade on cardiovascular risk in patients with psoriasis or arthritis remain controversial. Several monoclonal antibodies targeting costimulatory molecules have also been developed, a direct way to confirm their involvement in atherothrombotic cardiovascular diseases. Blocking the CD28CD80/86 axis with Abatacept has been shown to reduce cardiovascular risk. In contrast, the treatment of cancer patients with antibodies blocking immune checkpoint inhibitory receptors, such as CTLA-4, PD1, or PDL1, could worsen the risk of atherothrombotic events. In the future, cardiologists will be increasingly solicited to assess the cardiovascular risk of patients suffering from chronic inflammatory diseases or cancer and participate in choosing the most appropriate treatment. At the same time, immunomodulatory approaches directly targeting cardiovascular diseases will be developed as a complement to the usual treatment strategies.

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)

  • M. Sampi et al.

    Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis

    J. Am. Coll. Cardiol.

    (2008)
  • A. Knutsson et al.

    Associations of interleukin-5 with plaque development and cardiovascular events

    JACC Basic Transl Sci

    (2019)
  • H. Tilg et al.

    Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55

    Blood

    (1994)
  • H.G. Rus et al.

    Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall

    Atherosclerosis

    (1996)
  • T.B. Harris et al.

    Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly

    Am. J. Med.

    (1999)
  • H.R. Conti et al.

    Host responses to Candida albicans: Th17 cells and mucosal candidiasis

    Microb. Infect.

    (2010)
  • L. Wei et al.

    IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner

    J. Biol. Chem.

    (2007)
  • T. van Es et al.

    Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice

    Biochem. Biophys. Res. Commun.

    (2009)
  • R. Ross

    Atherosclerosis-an inflammatory disease

    N. Engl. J. Med.

    (1999)
  • E.J. Armstrong et al.

    Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies

    J Am Heart Assoc

    (2013)
  • K. Bengtsson et al.

    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.

    (2017)
  • J.M. Gelfand et al.

    Risk of myocardial infarction in patients with psoriasis

    J. Am. Med. Assoc.

    (2006)
  • J.C. Mason et al.

    Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions

    Eur. Heart J.

    (2015)
  • J.A. Avina-Zubieta et al.

    Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies

    Ann. Rheum. Dis.

    (2012)
  • C. Turesson et al.

    Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis

    Ann. Rheum. Dis.

    (2007)
  • P.M. Ridker et al.

    Antiinflammatory therapy with canakinumab for atherosclerotic disease

    N. Engl. J. Med.

    (2017)
  • P.M. Ridker et al.

    Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction

    Circulation

    (2000)
  • R.A. Allen et al.

    Polymorphisms in the TNF-alpha and TNF-receptor genes in patients with coronary artery disease

    Eur. J. Clin. Invest.

    (2001)
  • C. Monaco et al.

    Anti-TNF therapy: past, present and future

    Int. Immunol.

    (2015)
  • L.T. Jacobsson et al.

    Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis

    J. Rheumatol.

    (2005)
  • L. Ljung et al.

    Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis

    Ann. Rheum. Dis.

    (2016)
  • M.N. Di Minno et al.

    Carotid intima-media thickness in psoriatic arthritis: differences between tumor necrosis factor-alpha blockers and traditional disease-modifying antirheumatic drugs

    Arterioscler. Thromb. Vasc. Biol.

    (2011)
  • O. Ahlehoff et al.

    Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study

    J. Intern. Med.

    (2013)
  • J.J. Wu et al.

    Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis

    Arch. Dermatol.

    (2012)
  • A. Nast et al.

    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.

    (2015)
  • S. Prodanovich et al.

    Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis

    J. Am. Acad. Dermatol.

    (2005)
  • J.D. Greenberg et al.

    Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis

    Ann. Rheum. Dis.

    (2011)
  • M. Feldmann et al.

    Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?

    Annu. Rev. Immunol.

    (2001)
  • W.G. Dixon et al.

    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.

    (2007)
  • P.M. Ridker et al.

    Low-dose methotrexate for the prevention of atherosclerotic events

    N. Engl. J. Med.

    (2019)
  • P.M. Ridker

    Anticytokine agents: targeting interleukin signaling pathways for the treatment of atherothrombosis

    Circ. Res.

    (2019)
  • D.L. Mann

    Innate immunity and the failing heart: the cytokine hypothesis revisited

    Circ. Res.

    (2015)
  • E.S. Chung et al.

    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

    (2003)
  • P. Duewell et al.

    NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

    Nature

    (2010)
  • H. Shimokawa et al.

    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.

    (1996)
  • H. Kirii et al.

    Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice

    Arterioscler. Thromb. Vasc. Biol.

    (2003)
  • C.A. Dinarello et al.

    Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

    Nat. Rev. Drug Discov.

    (2012)
  • J.G. Stegger et al.

    Single nucleotide polymorphisms in IL1B and the risk of acute coronary syndrome: a Danish case-cohort study

    PloS One

    (2012)
  • L. Zhou et al.

    Associations between interleukin-1 gene polymorphisms and coronary heart disease risk: a meta-analysis

    PloS One

    (2012)
  • H.J. Lachmann et al.

    Use of canakinumab in the cryopyrin-associated periodic syndrome

    N. Engl. J. Med.

    (2009)
  • Cited by (8)

    • Prognostic impacts of Lipoxin A4 in patients with acute myocardial infarction: A prospective cohort study

      2023, Pharmacological Research
      Citation 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: CardioOncology
      Citation 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.

    View all citing articles on Scopus
    1

    Co-corresponding authors

    View full text