Neutrophil–lymphocyte ratio in the immune checkpoint inhibitors-related atherosclerosis

This commentary refers to ‘The neutrophil–lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials’, by N.H. Adamstein et al., doi:10.1093/eurheartj/ehaa1034 and the discussion piece ‘The neutrophil-lymphocyte ratio: considerations for clinical application’, by N.H. Adamstein and P.M. Ridker, doi:10.1093/eurheartj/ehab166. Atherosclerosis is a lipid-driven inflammatory process with potentially huge impact on public health, for which numerous biomarkers have been identified to predict its risk.1 Adamstein et al.2 demonstrated that the neutrophil–lymphocyte ratio (NLR), an immune cell-based and readily available biomarker, is an independent predictor of atherosclerotic cardiovascular (CV) risk and monitor the anti-inflammatory therapeutic effect. Recently, both clinical and basic studies have reported that the use of immune checkpoints inhibitors (ICIs) in patients with cancer may accelerate the progression of atherosclerosis and correlated with a higher CV risk.3 ICIs exert their effects at immune checkpoint proteins, releasing the natural brakes on T-cell activation, and promote potent antitumor immune responses.4 Compared to the phenotype of atherosclerosis mediated by traditional CV risk factors, ICI-related atherosclerosis appears to be exhibit greater levels of immune-mediated responses underlying its pathogenesis. Interestingly, NLR, an inflammatory biomarker suggested by Adamstein et al.,2 is based directly on immune cell numbers and has the potential to serve as a bridge between immune status and atherosclerosis. Alterations in the immune cell status and progression of atherosclerotic plaque by ICIs may be reflected by NLR levels. However, to the best of our knowledge, there is no publication evaluating the predictive or monitoring value of NLR in the ICI-related atherosclerosis. In a similar setting associated with ICI, Drobni et al.5 did observe significantly higher levels of NLR in patients with ICI-related myocarditis compared to those who did not develop this complication. This indicates the potential applicability of NLR for risk stratification purposes in immune-related phenomena following the use of ICIs, especially in ICI-related atherosclerosis. According to Adamstein et al.,2 an increasing NLR was associated with a higher CV risk, which attributed to the crucial role in the plaque progression played by myeloid cells, especially neutrophils. However, unlike the common myeloid-predominate phenotype, the immune cell composition of atherosclerotic plaque was modified by ICI, which aggravated towards a lymphocyte-predominate phenotype. After a short-term treatment with ICI, an increasing number of activated T cell was also detected in the blood of atherosclerotic mice.4 Alterations in immune cell spectrum may serve as the culprit of higher CV risk and subsequently influence the predictive value of NLR in the ICI-related atherosclerosis. Whilst compared with myocarditis, ICI-related atherosclerosis has a lower fatality rate; it may nevertheless affect more patients and therefore represents a healthcare burden with the increased survival of cancer patients. Therefore, an optimal biomarker is warranted to monitor the CV risk before, during, and after the ICI administration. We speculate that if NLR can fulfil this role and this should be explored in future population-based studies or clinical trials. Conflict of interest: none declared.