Complementariedad hidrófoba de las secuencias de la región determinante 3 (CDR3) que dilucidan los efectos...

Immune checkpoint inhibitors (ICIs) have significantly changed cancer treatment, demonstrating strong efficacy across multiple cancers. However, their use also carries the risk of serious immune-related side effects (irAEs), especially cardiotoxicity. To understand how these adverse effects occur, we studied peripheral blood mononuclear cells and T cells taken from the heart tissue of cancer patients who experienced cardiotoxicity during ICI therapy. Using spectral flow cytometry, single-cell RNA sequencing, and T cell receptor (TCR) sequencing, we found key differences in the immune profiles of affected patients. Those with cardiotoxicity had a noticeable increase in circulating CD4 + FOXP3 + and CD8 + PRF1 + T cells at disease onset. Our results also show that effector CD8 T cells are present in the heart tissue and pericardial fluid of patients with myocarditis, highlighting their role in starting the disease. TCR sequencing revealed expansions of CD8 GZMK + GZMA + and CD8 PRF1 + GZMA + T cells in myocarditis patients, along with increased activation markers CD69 and KLRG1, supporting the idea that specific cytotoxic CD8 T cell groups promote inflammation. Notably, we also found that T cells from patients with irAE myocarditis have shorter TCR CDR3 sequences, with a higher proportion of hydrophobic residues. This discovery suggests a new mechanism for TCR involvement in irAE myocarditis, focusing on T cell activation through the TCR's functional promiscuity, which relies more on TCR-MHC interactions than on specific peptide features. Overall, this research provides a foundation for new strategies targeting TCR physical properties to reduce risks and develop more precise therapies for vulnerable patients.