Immune checkpoint inhibitor-induced myocarditis is dependent on CD8 T cell-derived TNF and TNFR2 signaling - PubMed
9 hours ago
- #CD8 T cells
- #Myocarditis
- #Immunotherapy
- Immune checkpoint inhibitors (ICIs) improve cancer survival but can cause severe immune-related adverse events, including fatal myocarditis.
- A mouse model with cardiomyocyte-restricted antigen expression was developed to study ICI-induced cardiac autoimmunity.
- Combined αCTLA-4 and αPD-1 blockade led to expansion of antigen-specific CD8 T cells, myocardial inflammation, and lethal arrhythmias.
- PD-1 blockade alone allowed priming of autoreactive CD8 T cells, while CTLA-4 inhibition worsened cardiac pathology.
- Myocardial injury was independent of perforin-mediated cytotoxicity but depended on T cell-derived TNF and TNFR2 signaling.
- Blocking CD8 T cell-derived TNF or TNFR2 prevented cardiotoxicity without compromising antitumor efficacy.
- The study identifies TNF-TNFR2 signaling as a key mechanism in ICI myocarditis, offering a potential therapeutic target.