PROJECT ABSTRACT Merkel cell carcinoma (MCC) is a rare, highly aggressive, neuroendocrine carcinoma of the skin. Notably, approximately half of all MCC patients with advanced or metastatic disease respond to anti-PD1/PD-L1 as a first-line immunotherapy treatment, making it one of the most responsive solid tumors to immune checkpoint blockade (ICB). The initial response rate strongly suggests that immune system function is critical for recognizing and attacking MCC cells and perhaps can be restored and activated. Another interesting feature of MCC is that there are two distinct disease etiologies. In a majority of MCC tumors, there is clonal integration of Merkel cell polyomavirus (MCPyV) and expression of the viral antigens small T antigen (ST) and a truncated large T antigen (tLT) that drive oncogenesis. The nonviral subset of MCC (MCCN) is driven by UV damage and has a high mutational burden. In polyomavirus-positive MCC (MCCP), the viral antigens allow investigation into the adaptive immune response in a cancer setting. Indeed, studies have extensively characterized the CD8+ and CD4+ T cells that recognize large T antigen peptides in MCCP. Some MCC studies indicate that the presence of circulating and tumor infiltrating MCPyV specific T cells can improve overall survival. However, there is conflicting data to support that overall survival and response to immunotherapy are strongly correlated to CD8+ T cell infiltration. Therefore, other immune cells in the tumor microenvironment of MCC may be contributing to an antitumor response either directly through effector functions or indirectly through modulating T cell activity. Recently, tertiary lymphoid structures, whose formation is driven by the recruitment of B cells, were identified in both MCCP and MCCN subtypes and were associated with a favorable prognostic outcome. Aside from their documented presence in MCC tumors, the role of B cells in MCC is not well understood. Tumor- infiltrating B cells (TIL-Bs) are an emerging area of interest in cancer immunology. TIL-Bs can have pleiotropic roles in tumor immunity that affect overall survival and immunotherapy response in many cancer types. However, what defines the pro or antitumor role of B cells in the tumor microenvironment may depend on which B cell subsets are present, their frequency, and where they are localized in the tumor microenvironment. Given that both subtypes of MCC are highly responsive to ICB and that immune activation is potent in MCC, I hypothesize that TIL-Bs in the tumor microenvironment will have characteristics of antitumor immunity and will have a direct antigen-specific response to drive antitumor immunity. I will investigate this hypothesis with the following aims: 1) Determine the landscape of B cells in the tumor microenvironment of MCC and 2) Characterize the antigen specific responses of B cells in MCC.