Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Pathway in High-Risk Lymphocytic Acute Myocarditis

Abstract

Background The programmed cell death-1 (PD-1)/programmed cell death-ligand-1 (PD-L1) pathway is affected in immune checkpoint inhibitor (ICI)-associated acute myocarditis (AM), while this pathway in non-ICI-associated lymphocytic AM (LAM) is unexplored. Objectives This study aimed to assess cardiac levels of PD-L1/PD-1 in patients with high-risk LAM, compared with cardiac sarcoidosis (CS), non-inflammatory cardiomyopathy (non-Infl CMP), ICI-AM, and acute cellular rejection (ACR). Methods PD-L1 expression was measured with a visual semiquantitative scale from 0 (0%) to 5 (≥75% of cardiomyocytes), and PD-1 from 0 (0%) to 5 (≥75% of inflammatory cells) in 142 patients with cardiac histology. We compared patients with LAM (n = 39), CS (n = 26), non-InflCMP (n = 11). As an additional group, we included 8 patients with ICI-AM. Finally, the expression of PD-L1/PD-1 was also evaluated in heart transplant recipients with ACR of grade ≥2R (n = 28) or no ACR (n = 30). Results Patients with LAM had increased median levels of PD-L1 compared with CS or non-Infl-CMP: 2 (first to third quartile: 2-3) vs 1 (1-2) vs 0 (0-0), respectively; P < 0.0001. Likewise, PD-L1 expression was higher in those with ACR ≥2R vs no ACR. Conversely, PD-1 was blunted in LAM compared to ACR ≥2R. Patients with LAM had similar cardiac PD-L1 expression but reduced cardiac PD-1 expression compared with ICI-AM. Conclusions PD-L1 is overexpressed in cardiomyocytes of patients with LAM compared with non-Infl-CMP or focal non-lymphocytic myocarditis, such as CS, suggesting that cardiac PD-L1 expression is likely a response to T-cell-mediated injury. PD-1 expression is blunted in infiltrating inflammatory cells in LAM compared with ACR, suggesting a disruption of the PD-L1/PD-1 axis in LAM.