Dataset Information

Spatially organized inflammatory myeloid-CD8+ T cell aggregates linked to Merkel-cell Polyomavirus driven Reorganization of the Tumor Microenvironment

ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive skin cancer with high propensity for metastasis, caused by Merkel cell polyomavirus (MCPyV), or chronic UV-light-exposure. How MCPyV modulates immune responses within the tumor microenvironment and how such are linked to patient outcomes remain unknown partly due to technical barriers to understanding the spatial organization of the tumor microenvironment at single-cell resolution. We interrogated the cellular and transcriptional landscapes of 60 MCC-patients using Co-detection-by-indexing (CODEX) and targeted bulk RNA sequencing. Notably, we identified an enrichment of dysfunctional T cells spatially associating with CXCL9+ myeloid cells at the tumor invasive front as key feature of virus-positive MCC. While MCPyV-positivity and CD8+ T cell infiltration correlated with metastasis-free-survival, responses to immune checkpoint blockade were high regardless of virus-status. Instead, we found an enrichment of central memory T cells within tertiary-lymphoid-structures that associated with response to immune-checkpoint blockade. These findings highlight fundamental differences in the organization of the native tumor microenvironment of virus-positive MCC, that are linked to differential survival outcomes and could be used for personalized treatment strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281260 | GEO | 2024/11/11

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

Spatially organized inflammatory myeloid-CD8+ T cell aggregates linked to Merkel-cell Polyomavirus driven Reorganization of the Tumor Microenvironment

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets