STING promotes CD8 T-cell cardiotropism and fibrosis from distinct cellular compartments in doxorubicin cardiomyopathy.

AIMS: Doxorubicin (DR), a widely prescribed chemotherapy, has an unfortunate side effect of cardiotoxicity resulting from DNA damage and cardiac cell death. Cardiac atrophy, fibrosis and a cytotoxic CD8+ T-cell response, alongside increased cardiac and circulating interferon-inducible chemokines are hallmarks for DR cardiotoxicity.

METHODS AND

RESULTS

We discovered that the activation of the stimulator of interferon genes (STING) in several distinct cardiac cell compartments is central to CD8+ T-cell cardiotropism and DR cardiotoxicity. DR activates STING in cardiac fibroblasts, endothelial cells (ECs), and myeloid cells in vivo and in vitro. Myeloid STING is required for CD8+ T-cell activation and cardiotropism, whereas EC-STING mediates CD8+ T-cell cardiotropism towards CXCL9/10 and transendothelial migration. In contrast, cardiac fibroblast STING is dispensable for the cardiac CD8+ T-cell immune response but drives fibroblast transformation. We report CXCR3+ T cells and CXCL9/CXCL10 are more abundant in the hearts of DR cardiotoxicity patients.

CONCLUSION

Our work positions STING as a cell-specific driver of CD8+ T-cell cardiac inflammation and fibroblast activation in DR cardiotoxicity.