Dataset Information

Mechanisms of augmented tumor immunogenicity via ATR inhibition in Merkel cell carcinoma

ABSTRACT: There is an urgent unmet need to develop novel therapeutic strategies for tumors that do not respond to immune checkpoint inhibition (ICI) via PD-1 pathway blockade. The ATR-mediated DNA replication checkpoint has been reported to have immune-augmenting properties; however, the mechanisms underlying these properties are not well characterized. Here we explore the potential immunogenic effects of ATR inhibition in Merkel cell carcinoma (MCC), a cancer that is particularly relevant due to its high proliferative index and frequent response to anti-PD-(L)1 therapy. ATR inhibition induced tumor cell cytotoxicity in both Merkel cell polyomavirus-positive and UV-induced MCC cell lines in the absence of exogenous DNA damage. ATR inhibition alone or in combination with low-dose radiation induced numerous proinflammatory TNF-NF-κB signals as assessed via bulk transcriptomic profiling. These included increased expression of MHC class-I alleles, antigen processing machinery, interleukins, chemokines and interferon genes associated with anti-tumor immune responses in diverse tumor types. In parallel, we observed enhanced surface exposure of the “eat-me” signal calreticulin on MCC cells and subsequent phagocytosis by human monocyte-derived macrophages. Given that MCC tumors are often cGAS-STING-deficient (including two cell lines examined here), these ATRi-induced mechanisms are significant as they were activated regardless of cGAS-STING functional status. These data provide a mechanistic basis for the clinical evaluation of ATRi in advanced ICI-refractory MCC (NCT05947500), and suggest biomarkers that may be associated with response in human MCC tumors treated with ATRi.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317774 | GEO | 2026/01/27

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other
	GSE317774_gene_count_matrix.csv.gz	Csv

Items per page:

1 - 2 of 2

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

Mechanisms of augmented tumor immunogenicity via ATR inhibition in Merkel cell carcinoma

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets