PB0843 - The effect of immune checkpoint modulation on experimental atherosclerosis: a systematic review and meta-analysis of preclinical studies

Monday, June 24, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

AS

Anniek Strijdhorst

MD, PhD student
Amsterdam University Medical Centers, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands

Co-Author(s)

WV

Winnie G. Vos

PhD student
Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
KD

Kim E. Dzobo

Postdoc
Mayo Clinic, Rochester, Minnesota, United States of America
Rochester, Minnesota, United States
LB

Laura Bosmans

PhD, post-doc
Amsterdam University Medical Centers, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
PK

Pascal Kusters

MD, PhD
Department of Pathology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
NH

Nordin M.J. Hanssen

MD, PhD
Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
JK

Jeffrey Kroon

Assistent professor, PhD
Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
EL

Esther Lutgens

Professor, MD, PhD
Cardiovascular Medicine, Mayco Clinic, Rochestor, Minnesota
Rochester, Minnesota, United States
Hv

Hanneke W. M. van Laarhoven

Professor, MD, PhD
Department of Medical Oncology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
TS

Tom T.P. Seijkens

MD, PhD
Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
Nick van Es, MD PhD

Internist-vascular medicine
Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
Amsterdam, Noord-Holland, Netherlands

Background: Patients with cancer treated with immune checkpoint inhibitors have a 2-3-fold increased risk of arterial thromboembolism. The mechanism is incompletely understood but may involve enhanced plaque inflammation and, subsequent, progression of atherosclerosis.

Aims: To assess the effects of modulation of inhibitory immune checkpoint proteins (ICPs) on increased plaque inflammation and hence atherosclerosis progression in preclinical animal models.

Methods: A systematic review was performed using MEDLINE, Embase, Web of Science, and Scopus up to September 2023. Studies were eligible if they evaluated the effect of inhibition or stimulation of PD-1, PD-L1, CTLA-4, or LAG-3 on atherosclerotic plaque size in animal models. Secondary outcomes were plaque composition and systemic inflammation. Ratios of means (ROM) across the studies were pooled in a random effects meta-analysis.

Results: Twelve out of 1655 identified studies were included. All studies used an atherosclerotic mouse model and either evaluated inhibition (n=8) or stimulation of ICPs (n=4). Upon ICP inhibition, using either pharmacological inhibition or genetic deficiency models, atherosclerotic plaque size was 38% higher in treated mice compared to control mice (ROM 1.41; 95%-CI 1.16-1.73, Figure 1). Plaque composition after inhibition was characterized by more abundant CD4+ T cells, CD8+ T cells, and pro-inflammatory macrophages compared to control mice. Treated mice exhibited a more activated T cell profile in peripheral blood and lymphoid organs compared to control mice. Upon stimulation of ICPs, opposite results were observed: atherosclerotic plaque size was 28% lower in treated mice compared to controls (ROM 0.72; 95%-CI 0.65-0.80). This was paralleled by a reduction in inflammatory cells in plaques and systemic inflammation.

Conclusion(s): Immune checkpoint inhibition leads to significantly increased atherosclerotic plaque size, lesional inflammation and systemic inflammation in mice. This may be the underlying mechanism of the increased risk of arterial thromboembolism in patients with cancer who are treated with immune checkpoint inhibitors.