JACC. Advances · 2026
Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Pathway in High-Risk Lymphocytic Acute Myocarditis.
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Ammirati Enrico, Gallone Guglielmo, Veronese Giacomo, Adler Eric D, Mäyränpää Mikko I, Bonoldi Emanuela, Petrella Duccio, Kim Paul J, Brambatti Michela, Vaira Matteo Pio, Rybczynski Meike, Milting Hendrik, Michel-Behnke Ina, Gatto Fernando, Schlotter Florian, Thiele Holger, Cruz Rodriguez Jose Benjamin, Luchner Andreas, Grabmaier Ulrich, Massberg Steffen, Schuchlenz Herwig, Ebner Christian, Rassaf Tienush, Linke Axel, Heidecker Bettina, Manuylova Tatiana, Garascia Andrea, Moslehi Javid J, Lehtonen Jukka Y, Klingel Karin
Аннотация
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.
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.