Impact of the autoantibody reactome on disease outcomes in Merkel cell carcinoma

Summary: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a mortality of ~30%. In 80% of cases, MCC arises from integration of the Merkel cell polyomavirus (MCPyV) and expression of viral oncoproteins. Immune checkpoint inhibitors benefit ~50% of patients with advanced disease, but new therapeutic approaches are still needed to address recurrent and resistant disease. To gain insight into potential novel targets for MCC therapy, we sought to understand the potential impacts that natural patient autoantibodies may exert on disease outcomes. While prior studies have identified a protective role of MCPyV-specific B cells, the role of autoantibodies in MCC anti-tumor immunity has not been characterized. Rapid Extracellular Antigen Profiling (REAP), a high-throughput yeast surface protein display-based assay, allows for the identification of autoantibodies targeting ~6,500 different extracellular and secreted proteins. Using REAP, we screened antibodies isolated from 444 MCC patient serum/plasma samples collected within 3 months of diagnosis (avg. 36 days) to identify trends in the autoantibody reactome that associate with disease extent and patient outcomes. By performing Cox proportional hazard ratio analyses, we identified autoantibody responses that were associated with both enhanced (HR < 0.5) and diminished (HR > 2) survival outcomes. These autoantibodies target a diverse set of protein antigens including immunoregulatory cytokines and serine protease pathways that potentially modulate the tumor microenvironment. Ongoing studies aim to biochemically validate the functional effects of autoantibodies on their antigen targets and to isolate and phenotype circulating B cells that recognize autoantigens. Allison J. Remington¹, Yvonne Hsu¹, Kai Qin¹, Rian Alam², Macy W. Gilmour², Paul Nghiem², Aaron M. Ring¹ 1. Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, United States. 2. Department of Dermatology, University of Washington, Seattle, WA, United States. Adaptive and Auto-Immunity