Immune checkpoint inhibitor treatment and atherosclerotic cardiovascular disease: an emerging clinical problem

Abstract

Antibody-mediated blockade of co-inhibitory molecules such as cytotoxic T lymphocyte-associated protein 4, PD1 and PDL1 elicits potent antitumor responses and improves the prognosis of many patients with cancer. As these immune checkpoint inhibitors (ICIs) are increasingly prescribed to a diverse patient population, a broad range of adverse effects is emerging. Atherosclerosis, a lipid-driven chronic inflammatory disease of the large arteries, may be aggravated by ICI treatment. In this review, we discuss recent clinical studies that analyze the correlation between ICI use and atherosclerotic cardiovascular disease (CVD). Indeed, several studies report an increased incidence of atherosclerotic CVD after ICI administration, with the occurrence of pathologies such as myocardial infarction, ischemic stroke and coronary artery disease significantly higher after ICI use. Increased awareness and better monitoring of ICI-treated patients can elucidate risk factors that contribute to ICI-induced aggravation of atherosclerosis and identify promising treatment strategies. For now, optimal cardiovascular risk assessment is required to protect ICI-receiving patients and long-term survivors of cancer from the detrimental effects of ICI therapy on atherosclerotic CVD.

Keywords: immunotherapy; inflammation; review.

Figure 1

Effects of antibody-mediated blockade of CTLA4 and PD1 in Ldlr^−/− mice. Immune checkpoint inhibitors inhibit CTLA4 and PD1 signaling and thereby promote activation of both splenic and circulating CD8⁺ T cells. Endothelial activation markers VCAM1 and ICAM1 are upregulated and facilitate the influx of CD8⁺ T cells into the vessel wall. Once they have entered the lesion, CD8⁺ T cells induce macrophage death and increase the T-cell:macrophage ratio, thus driving lymphoid-driven plaque inflammation. Together, this promotes plaque progression. CTLA4, cytotoxic T lymphocyte-associated protein 4; PD1, programmed cell death protein 1.