Altered PDL1 signaling after doxorubicin-treatment in murine hearts

Background Survival rates in the context of cancer have seen substantial improvements, primarily attributed to advancements in therapeutic strategies and novel immunomodulatory medications. There has been a growing interest in combining anthracyclines with immune checkpoint inhibitors (ICIs) to enhance the elimination of cancer cells. However, concerns have arisen for prior anthracycline exposure to render the heart more susceptible to increased toxicity from subsequent ICI treatments, including anti-programmed cell death protein 1 (PD1) inhibitors.

Methods & Results We employed a high-dose anthracycline mouse model (20 mg/kg; 55 mg/m²) to investigate the involvement of the PD1 immune checkpoint signaling pathway within cardiac tissue. Exposure to anthracycline treatment resulted in a decline in cardiac function at d6 after injection as measured by echocardiography (EF: 6 %pt decrease, FS: 4 %pt points decrease) and a rise in cardiac damage biomarkers (CK 27-fold, cTnI 4-fold increase). Flow cytometric analysis revealed a shift in the composition of cardiac cell populations, marked by a reduction in cardiomyocytes and an increase in fibroblasts. Concurrently, at the same time point, there was a notable reduction in the quantity of PD1 ligand (PDL1)-positive immune cells, endothelial cells fibroblasts and cardiomyocytes within the cardiac tissue, as well as an increase of PD1⁺ immune cells. These findings were further validated using immunohistological and western blot analysis.

Conclusion We could show that PD1/PDL1 signaling is indeed derailed in the heart following anthracycline treatment. This is associated with decreased cardiac function. Further studies need to address the implications of combined anthracycline/PD1 therapies on the heart and whether it can be remedied using standard of care medication.