Circulating Neoplastic-Immune Hybrid Cells Predict Metastatic Progression in Uveal Melanoma

SIMPLE SUMMARY: Uveal melanoma is an aggressive cancer that begins in the eye, but often spreads to distant organs when tumor cells enter the blood. Disease spreads in nearly half of uveal melanoma patients, and is fatal. We discovered a new tumor cell population in the blood stream of cancer patients that has combined tumor cell and white blood cell features. These cells, called circulating hybrid cells, can develop into metastatic tumors. Recently, we detected circulating hybrid cells in the blood of patients with uveal melanoma. In this study we determine that the number of circulating hybrid cells in the blood at time of initial treatment of uveal melanomas predicts future development of disease spread. Circulating hybrid cells have promise as a non-invasive and repeatable “liquid biopsy” for uveal melanoma patients. Therefore, study of this newly discovered cancer cell will improve understanding of the biology of disease progression in uveal melanoma. ABSTRACT: Background: Uveal melanoma is an aggressive cancer with high metastatic risk. Recently, we identified a circulating cancer cell population that co-expresses neoplastic and leukocyte antigens, termed circulating hybrid cells (CHCs). In other cancers, CHCs are more numerous and better predict oncologic outcomes compared to circulating tumor cells (CTCs). We sought to investigate the potential of CHCs as a prognostic biomarker in uveal melanoma. Methods: We isolated peripheral blood monocular cells from uveal melanoma patients at the time of primary treatment and used antibodies against leukocyte and melanoma markers to identify and enumerate CHCs and CTCs by immunocytochemistry. Results: Using a multi-marker approach to capture the heterogeneous disseminated tumor cell population, detection of CHCs was highly sensitive in uveal melanoma patients regardless of disease stage. CHCs were detected in 100% of stage I-III uveal melanoma patients (entire cohort, n = 68), whereas CTCs were detected in 58.8% of patients. CHCs were detected at levels statically higher than CTCs across all stages (p = 0.05). Moreover, CHC levels, but not CTCs, predicted 3 year progression-free survival (p < 0.03) and overall survival (p < 0.04). Conclusion: CHCs are a novel and promising prognostic biomarker in uveal melanoma.