Immune Checkpoint Inhibitor Associated Myocarditis Occurs in Both High-Grade and Low-Grade Forms

Abstract

Immune checkpoint inhibitor (ICI) therapy for malignancy has been associated with adverse events including myocarditis. It has been unclear if there are distinct pathologic grades of ICI associated myocarditis (ICIM) and if such grades are associated with distinct clinical outcomes. Cardiac tissue from 10 patients with ICIM (9 biopsies and 1 autopsy) were evaluated using immunohistochemistry for CD3, CD8, CD68, tryptase, PD-L1 and C4D. The cases were divided into two groups based on the density of CD3+ T cells: high-grade ICIM (H-ICIM, >50 CD3+ cells/hpf) or low-grade ICIM (L-ICIM, ≤50 CD3+ cells/hpf). The densities of macrophages, T cells, eosinophils, necrotic myocytes and PD-L1+ macrophages and myocytes were compared between the two groups and with thirteen cases of grade 2R acute cellular allograft rejection (ACR). Three patients were classified as H-ICIM and seven as L-ICIM. There were higher densities of CD3+ cells and CD8+ cells in H-ICIM and ACR compared with L-ICIM. The number of CD68+ macrophages was higher in H-ICIM compared with L-ICIM and ACR. For both H-ICIM and L-ICIM, there was a higher CD68/CD3 ratio and higher density of PD-L1+ macrophages and myocytes compared with ACR. Clinically, there were trends towards higher serum troponin levels, shorter interval from first ICI treatment, and more frequent female gender in the H-ICIM group compared with the L-ICIM group. All the patients with H-ICIM died, while all the patients with L-ICIM were still living. These data suggest that ICIM occurs in two forms, a high-grade form with increased inflammatory cell infiltration and a more fulminant clinical course, and a low-grade form with a lower degree of inflammatory cell infiltration and a more indolent clinical course. Compared with grade 2R ACR, ICIM is characterized by a more lymphohistiocytic inflammatory infiltrate with an increased CD68/CD3 ratio and increased PD-L1+ macrophages and myocytes.