Title: Molecular and Immunological Mechanisms Underlying Merkel Cell Polyomavirus-Associated Merkel Cell Carcinoma
Abstract:
Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin cancer with a mortality rate of approximately 33-46%. Roughly 80% of cases are caused by Merkel cell polyomavirus (MCPyV), a virus that infects most adults but rarely drives malignant transformation, while the remaining cases arise from chronic ultraviolet (UV) damage. Despite these distinct origins, both forms produce the same aggressive tumor phenotype. This review examines the molecular and immunological events that allow a usually benign infection to give rise to cancer in rare circumstances. In virus-positive disease, integration of MCPyV DNA into the host genome traps the virus in a non-replicative state, and tumor-associated mutations truncate the Large T (LT) antigen, disabling the Retinoblastoma protein (pRb) without triggering a p53-mediated stress response. The intact Small T (sT) antigen further sustains proliferative signaling. Immune surveillance, particularly by CD8+ T cells, normally suppresses viral reactivation and clears early transformed cells, which is why MCC risk rises sharply in people with weakened immunity, including organ transplant recipients, patients with HIV, and older individuals experiencing immunosenescence. A central unresolved question is which cell type these events begin in. Merkel cells are post-mitotic and poorly suited to clonal expansion, whereas dermal fibroblasts and epidermal progenitor cells are mitotically active and may better account for viral tropism, integration, and the relatively open chromatin state observed in MCC tumors. Integrating findings from virology, immunology, and cancer biology, this review explains why MCC remains rare despite the prevalence of MCPyV and examines how the unresolved question of the cell of origin limits current understanding of the disease's initiation.
