Anthracycline Therapy Modifies Immune Checkpoint Signaling in the Heart

Cancer survival rates have increased significantly because of improvements in therapy regimes and novel immunomodulatory drugs. Recently, combination therapies of anthracyclines and immune checkpoint inhibitors (ICIs) have been proposed to maximize neoplastic cell removal. However, it has been speculated that a priori anthracycline exposure may prone the heart vulnerable to increased toxicity from subsequent ICI therapy, such as an anti-programmed cell death protein 1 (PD1) inhibitor. Here, we used a high-dose anthracycline mouse model to characterize the role of the PD1 immune checkpoint signaling pathway in cardiac tissue using flow cytometry and immunostaining. Anthracycline treatment led to decreased heart function, increased concentration of markers of cell death after six days and a change in heart cell population composition with fewer cardiomyocytes. At the same time point, the number of PD1 ligand (PDL1)-positive immune cells and endothelial cells in the heart decreased significantly. The results suggest that PD1/PDL1 signaling is affected after anthracycline treatment, which may contribute to an increased susceptibility to immune-related adverse events of subsequent anti-PD1/PDL1 cancer therapy.

Automated summary

Cancer survival rates have increased due to improvements in therapy regimes and immunomodulatory drugs. Combination therapies of anthracyclines and immune checkpoint inhibitors (ICIs) have been proposed to remove neoplastic cells. However, prior anthracycline exposure may make the heart vulnerable to increased toxicity from subsequent ICI therapy. This study shows that anthracycline treatment affects the PD1/PDL1 signaling pathway in cardiac tissue, potentially increasing susceptibility to immune-related adverse events of anti-PD1/PDL1 cancer therapy.