Immune cell profiling in atherosclerosis: role in research and precision medicine

Abstract

Inflammation is intimately involved at all stages of atherosclerosis and remains a substantial residual cardiovascular risk factor in optimally treated patients. The proof of concept that targeting inflammation reduces cardiovascular events in patients with a history of myocardial infarction has highlighted the urgent need to identify new immunotherapies to treat patients with atherosclerotic cardiovascular disease. Importantly, emerging data from new clinical trials show that successful immunotherapies for atherosclerosis need to be tailored to the specific immune alterations in distinct groups of patients. In this Review, we discuss how single-cell technologies -such as single-cell mass cytometry, single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing -are ideal for mapping the cellular and molecular composition of human atherosclerotic plaques and how these data can aid in the discovery of new precise immunotherapies. We also argue that single-cell data from studies in humans need to be rigorously validated in relevant experimental models, including rapidly emerging single-cell CRISPR screening technologies and mouse models of atherosclerosis. Finally, we discuss the importance of implementing single-cell immune monitoring tools in early phases of drug development to aid in the precise selection of the target patient population for data-driven translation into randomized clinical trials and the successful translation of new immunotherapies into the clinic.

Roles of Macrophages in Atherogenesis

“…In some cases, the studies have been complemented by time of flight mass cytometry analyses. Over the past 3 years, several groups have used scRNAseq to examine leukocyte heterogeneity in various mouse models of AS (Cochain et al, 2018;Kim et al, 2018;Winkels et al, 2018;Lin et al, 2019;Zernecke et al, 2020) and in human carotid AS (Fernandez et al, 2019) and these studies have been recently reviewed (Willemsen and de Winther, 2020;Fernandez and Giannarelli, 2021). ScRNAseq analyses of mouse atherosclerotic lesions identified three main clusters of the Mφs in AS, resident-like, inflammatory, and TREM2hi (Willemsen and de Winther, 2020).…”

Crosstalk Between Macrophages and Vascular Smooth Muscle Cells in Atherosclerotic Plaque Stability

“…Substantial advances in the field of bioinformatics, particularly in single-cell RNA sequencing, has provided detailed analysis of the transcriptome in individual cells and is beginning to validate the existence of cellular crosstalk within atherosclerotic plaques. 89 For instance, single-cell RNA sequencing has been used to profile the cellular landscape of atherosclerotic plaques from both humans and mice, revealing a larger diversity of immune cells in lesions than previously appreciated. In individuals with stroke, macrophages show high expression of CCL5, and interestingly, its interaction with its cognate receptor CCR5 on vSMCs drives proliferation, dedifferentiation, and vascular remodeling, demonstrating the presence of cell-cell communication within atherosclerotic plaques.…”

False Utopia of One Unifying Description of the Vulnerable Atherosclerotic Plaque: A Call for Recalibration That Appreciates the Diversity of Mechanisms Leading to Atherosclerotic Disease

“…The identification of the complex cell type composition and functional states of cells in atherosclerotic plaques is crucial for the identification of the cellular contribution to disease and of new druggable cellular targets. 63…”