Immune checkpoint inhibitor induces cardiac injury by impairing efferocytosis of macrophages via MerTK cleavage

Cancer immunotherapy is a well-established therapeutic approach for various types of cancer. However, its clinical utility is usually limited by cardiovascular adverse events. Immune Checkpoint Inhibitors (ICIs) can induce diverse forms of cardiotoxicity, with myocarditis being the most fatal complication. The underlying mechanism of its occurrence remains elusive. Therefore, this study aims to elucidate the impact of programmed death-1 (PD-1) inhibitor on myocarditis development in mice. Myeloid-epithelial-reproductive tyrosine kinase (MerTK) receptors, located on the surface of macrophages, play a pivotal role in phagocytic regulation. We established a mouse model of autoimmune myocarditis by injecting 6-week-old normal male BALB/c mice with PD-1 inhibitor and cardiac troponin I peptide fragments, which resulted in elevated levels of serum soluble MerTK (SolMer) and reduced numbers of MerTK-CD68 double-positive macrophages, accompanied by cardiac injury in mice. In vitro, PD-1 inhibitor promotes a disintegrin and metalloproteinase17 (ADAM17)-mediated shed of the MerTK, forming SolMer, through MKK3/P38 MAPK pathway, leading to downregulation of MerTK expression on the macrophage surface. This results in the inhibition of efferocytosis and impairment of tissue repair function, ultimately contributing to myocarditis development. TAPI-0 inhibited the activity of ADAM17, while SB203580 inhibited the phosphorylation of P38 MAPK. Both inhibitors effectively restored the inhibition of efferocytosis induced by the PD-1 inhibitor. In vitro, when the PD-1 receptor on the surface of RAW264.7 macrophages was knocked down and then stimulated with a PD-1 inhibitor, no further significant alterations in the pathway were elicited. In conclusion, the PD-1 inhibitor induces the shedding of MerTK in macrophages by binding to the PD-1 receptor on the surface of macrophages and activating the MKK3/P38 MAPK/ADAM17 pathway, leading to impaired efferocytosis. Elucidation of this molecular mechanism holds promise for improved prognosis and therapeutic strategies in cancer patients.