Immune checkpoint inhibitors, widely used in cancer therapy, have revolutionized oncology but come with the risk of severe immune-related adverse events, including checkpoint myocarditis. This potentially fatal condition arises from an immune system attack on heart tissue, yet its underlying mechanisms remain poorly understood. A recent study has shed light on immune responses in the heart, blood, and tumors of affected patients, providing new insights into the biology driving checkpoint myocarditis and identifying promising biomarkers.
The research team conducted an in-depth analysis of samples from 28 patients diagnosed with checkpoint myocarditis and 41 unaffected individuals. Using cutting-edge single-cell RNA sequencing, T-cell receptor (TCR) sequencing, and proteomics, the study mapped cellular interactions at an unprecedented resolution.
The findings revealed an increased presence and co-localization of cytotoxic T cells, conventional dendritic cells, and inflammatory fibroblasts in myocarditis-affected heart tissue. Meanwhile, blood analysis of 366,066 cells highlighted a significant reduction in plasmacytoid dendritic cells, conventional dendritic cells, and B-lineage cells. Notably, mononuclear phagocytes were more frequent in affected individuals.
A key discovery involved heart-expanded TCR clones in eight patients, which intriguingly did not target the cardiac autoantigens α-myosin, troponin I, or troponin T. Furthermore, TCRs enriched in heart tissue were largely distinct from those found in paired tumor tissue, suggesting an intricate interplay between antitumor immunity and cardiac autoimmunity. The presence of these heart-expanded TCRs in cycling blood CD8 T cells was linked to fatal outcomes in checkpoint myocarditis cases.
These findings emphasize the importance of cellular interactions and specific immune signatures in understanding checkpoint myocarditis. Importantly, the identification of potential biomarkers could pave the way for earlier diagnosis and targeted interventions to mitigate risk.
This research provides a critical step forward in understanding the balance between effective cancer treatment and managing immune-related complications, offering hope for improved outcomes in high-risk patients.
Reference: Blum SM et al. Immune responses in checkpoint myocarditis across heart, blood and tumour. Nature. 2024;636:215-23.
Anaya Malik | AMJ
