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B cells specific for polyomavirus-derived oncoprotein are predictive of Merkel cell carcinoma progression

ABSTRACT: Merkel cell carcinoma usually results from integration of an oncogenic version of the Merkel cell polyomavirus T-antigen. While T-antigen-specific antibodies are produced by most patients with T-antigen-driven MCC and are used to monitor disease recurrence, baseline antibody titers do not associate with MCC outcome. Here, we analyzed the frequency and phenotype of T-antigen-specific and total B cells from MCC patient blood and tumor samples in search of predictive biomarkers of disease outcome. While no blood-associated B cell phenotypes were strongly associated with disease outcome, the presence of detectable T-antigen-specific antibody-secreting and/or germinal center B cells in MCC patient tumor samples accurately predicted disease control. In vitro, B cells engineered to be specific for T-antigen were capable of robust activation T-antigen-specific CD4+ T cells. Together, these results show the predictive power of B cell responses in relation to MCC outcomes and may suggest that cancer-specific B cells enhance anti-tumor immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301498 | GEO | 2025/08/01

REPOSITORIES: GEO

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Project description:Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCC, may drive tumorigenesis via viral T antigens. However, mechanisms underlying pathogenesis in MCPyV-negative MCC remain poorly understood. To nominate genes contributing to pathogenesis of MCPyV-negative MCC, we performed DNA microarray analysis on 30 MCCs. MCPyV status of MCCs was determined by PCR for viral DNA and RNA. 1593 probe-sets were differentially expressed between MCPyV-negative and -positive MCC, with significant differential expression defined as at least 2-fold change in either direction and p-value of ≤ 0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8+ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may play an important role in tumorigenesis of MCPyV-negative MCC. Functional and clinical validation studies are needed to determine whether this tumor suppressor pathway represents an avenue for targeted therapy. We used microarrays to characterize global gene expression patterns related to Merkel cell polyomavirus status in Merkel cell carcinoma. Furthermore, we compared Merkel cell carcinoma to less aggressive primary cutaneous carcinomas. We utilized flash-frozen tumor tissue from primary Merkel cell carcinomas, metastatic Merkel cell carcinomas, primary cutaneous squamous cell carcinomas, and basal cell carcinomas. Merkel cell carcinoma cell lines, which represent a pure population of tumor cells, were also included. Merkel cell polyomavirus status was determined at the DNA and RNA level using multiple primers for viral T-antigen and capsid protein sequences. This Series represents two analyses - one with new Samples normalized together, and another with some of the new Samples re-normalized with Samples previously submitted under Series GSE13355. The latter group contain 'renormalized' in the titles.

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B cells specific for polyomavirus-derived oncoprotein are predictive of Merkel cell carcinoma progression

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