806 PD-1 blockade affects inflammation and metabolic flexibility to potentially mediate cardiac immune-related adverse events

Background Immune checkpoint blockade (ICB) is now a mainstay of cancer therapy with success in extending the survival time several cancers, including melanoma. Still, these modalities result immune-related adverse events (irAEs), approximately 80% melanoma patients experiencing toxicity. IrAEs can lead to treatment discontinuation, contributing mortality. In addition, one uncommon irAE high mortality rate ICB-related myocarditis. addition myocarditis, ICB also cause arrhythmias and heart failure. Currently, early markers predict cardiotoxicity are unknown. During cardiac insult, cardiomyocyte metabolic flexibility results reprogramming from fatty acid oxidation glycolysis overcome injury; however prolonged remodeling precedes most pathological alterations heart, suggesting that changes metabolism may contribute immunotherapy-related damage. Methods Male C57BL/6 mice were injected B16 cells. Once tumors reached 100 mm 3 , animals treated three doses anti-PD-1 antibody (200 µg IP). Echocardiograms performed prior necropsy using Vevo LAZR ultrasound assess function. Bulk RNA sequencing (RNA-seq) immunohistochemistry on tissue. Single-cell (scRNA-seq) was human peripheral blood mononuclear cells (PMBCs) therapy. Results Echocardiogram showed anti-PD1 attenuated stroke volume increase compared WT mice, be associated Histological examination no evidence inflammation. RNA-seq further examine mechanisms heart. Our data shows over 230 genes uniquely expressed tissue isotype control. While overt immune infiltrate seen, gene set enrichment analysis (GSEA) significant positive chemokine receptor interactions potentially playing role differentiation cardiac, cell populations.Furthermore, observed among pathways. Interestingly, upregulation PDK4 hearts antibody. activation restricts during stress. scRNA-seq patient PBMCs indicates an levels monocytic population after treatment, this protein regulated due blockade. Conclusions Cardiac inflammation implicated ICB-myocarditis However, suggest PD-1 alters pathways damage, potential identify irAEs Acknowledgements T32 Office The Director, National Institutes Health (T32-OD010957, SMB) (R21CA249349, DSP), American Cancer Society Research Scholar Grant (133727-RSG-19-150-01-LIB, DSP)