Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti–PD-1 Immune Checkpoint Inhibitor Cancer Therapy

Myocarditis has emerged as an immune-related adverse event of immune-checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. Our new NOD-cMHCI/II-/-.DQ8 mouse strain expresses human HLA-DQ8 in the absence of classical murine MHC class I and II. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis development. Using RNA sequencing analyses we performed a thorough characterization of cardiac and skeletal muscle infiltrating T-cells, identifying shared and unique characteristics of both populations. In order to determine the molecular features of heart and skeletal muscle infiltrating T-cells, and how those features may differ, we sorted CD90+ TCRβ+ T-cells from heart or skeletal muscle (diaphragm & soleus) of NOD-cMHCI/II-/-.DQ8 mice within one hour of a fourth injection of anti-PD-1 (administered twice a week starting at 10-12 weeks of age). We then performed gene expression analysis from RNA-seq data obtained from these heart or skeletal muscle T-cells. Each sequenced sample is derived from a pool of cells isolated from between 2-12 mice individual mice.