Spotlight on immune cell manipulations in atherosclerosis

Cardiovascular disease (CVD) remains one of the deadliest diseases worldwide. Atherosclerosis, a lipid-driven chronic inflammatory disease, results in plaque formation of the middle and large arteries and consequent rupture can lead to e.g. myocardial infarction. While optimal lipid-lowering strategies have greatly reduced the incidence of atherosclerotic CVD, a residual inflammatory risk remains. Here, we describe several alterations of the immune system and their corresponding results on atherosclerosis.
We identify that Casitas B-cell lymphoma proto-oncogene B (CBL-b), a natural inhibitor of T cell activation, is present in several immune cells in atherosclerotic plaques (e.g. macrophages, T cells) and that its expression is negatively correlated with plaque progression. Furthermore, CBL-b deficiency in Apoe^-/- mice exacerbated plaque area, a phenotype which could be rescued with CD8⁺ T cell depletion, indicating that Cblb^-/- CD8⁺ T cells drove the phenotype.
We then introduce immune checkpoint inhibitors (ICIs), which are antibodies against co-inhibitory molecules that have greatly revised the cancer field, as ICI treatment triggers potent anti-tumor responses. Nevertheless, we hypothesized that this over-activation of T cells could also aggravate atherosclerosis. Indeed, dual antibody-mediated blockade of CTLA4 and PD1 aggravated lesion size in LDLr^-/- mice, a find that could have serious ramifications for ICI-treated cancer patients.
Lastly, we examine the effect of PFK158 treatment, which inhibits PFKFB3, the rate-limiting enzyme of glycolysis, the main metabolic driver in pro-inflammatory immune cells. In both murine and human atherosclerotic lesions, PFKFB3 was mainly present in macrophages and endothelial cells and its expression was positively correlated to plaque progression. In LDLr^-/- mice, PFK158 treatment reduced plaque progression and stabilized the atherosclerotic lesions.