Identifying molecular targets for rational immunosuppressive strategies in patients with immune checkpoint therapy-induced myocarditis and myositis

2511 Background: Immune checkpoint therapies (ICTs) can induce durable anti-tumor responses but also life-threatening immune-related adverse events (irAEs). Myocarditis, myositis, and myasthenia gravis (MG) are rare, often concurrent irAEs with mortality up to 40%. Steroids are the standard first-line treatment and have significant adverse events with prolonged use. We and others have identified serum autoantibodies in these irAEs, suggestive of B cell contribution to pathogenesis. Furthermore, although prior studies have shown T cells and myeloid cells in inflamed muscle tissue, their specific subtype and role in disease pathogenesis have yet to be defined. This understanding may contribute to the development of more effective immunosuppressive strategies. Hypothesis: In addition to T cells, plasma B and myeloid cells contribute to the pathogenesis of ICT-induced myocarditis, myositis, and MG. Methods: We enrolled patients with suspected ICT-induced myocarditis, myositis, and MG on an IRB-approved laboratory protocol. Diagnosis required: 1) symptoms requiring hospitalization; 2) elevated serum markers (creatine kinase ≥5x normal, troponin >99th percentile or detection of autoantibodies for MG); and 3) positive biopsy, electromyography, or cardiac MRI. Patients underwent standard diagnostic testing (including endomyocardial and/or skeletal muscle biopsy) and treatment as clinically indicated. Results: 23 patients were enrolled (n=13, confirmed irAE; n=10, negative control). Most patients received combination ICT (10/13, 77%). Anti-striated muscle and/or acetylcholine receptor binding antibodies were detected in 7/13 patients (54%), including 3 without MG (known to have both T and B cell etiologies). Single cell RNA sequencing of patient tissue (confirmed irAEs: cardiac n=10, skeletal n=9; control: cardiac n=4, skeletal n=5) identified specific populations of myeloid and CD8 + T cells conserved between inflamed cardiac and skeletal muscle. Conclusions: Specific populations of T cells, myeloid cells, and plasma B cells are potential targets for rational immunosuppressive strategies in ICT-induced myocarditis and myositis and will be tested in murine models to inform future clinical trial design. [Table: see text]