Cancer-specific CD8 T cell frequency at baseline in blood correlates with response to PD-1 blockade in Merkel cell carcinoma.
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PROVIDER: PRJNA946694 | ENA |
REPOSITORIES: ENA
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Project description:Understanding immunotherapy resistance is challenging due to difficulty identifying cancer-specific T cells. Merkel cell carcinoma (MCC) is typically driven by Merkel cell polyomavirus (MCPyV), facilitating identification of cancer-specific T cells across patients. We characterized cancer-specific T cells in 35 MCC patients, including participants in a neoadjuvant anti-PD-1 trial. Higher MCPyV-specific CD8 T-cell frequency in pre-treatment blood (but not tumors) correlated with response (p=0.005). Single-cell transcriptomics revealed MCPyV-specific CD8 T cells in blood had increased stem/memory signatures and decreased exhaustion signatures relative to their intratumoral counterparts. While frequency of peripheral cancer-specific T cells was associated with response to initial PD-(L)1 blockade, longitudinal study of acquired resistance revealed immune evasion by tumor-cell MHC-I downregulation despite cancer-specific T cell expansion to 0.5% in blood. Blood thus appears to be an important reservoir of cancer-specific CD8 T cells and adoptive cell therapies may be particularly effective in patients without such cells.
2023-04-01 | GSE227708 | GEO
Project description:Cancer-specific CD8 T cell frequency at baseline in blood correlates with response to PD-1 blockade in Merkel cell carcinoma
| PRJNA942968 | ENA
Project description:Understanding immunotherapy response and resistance is challenging due to difficulty identifying cancer-specific CD8 T cells. Merkel cell carcinoma (MCC) is typically driven by Merkel cell polyomavirus (MCPyV), facilitating identification of cancer-specific T cells across patients. We characterized cancer-specific T cells in 35 MCC patients, including from a neoadjuvant anti-PD-1 trial. Higher MCPyV-specific CD8 T-cell frequency in pre-treatment blood (but not tumors) correlated with response (p=0.0056). Single cell RNAseq revealed MCPyV-specific CD8 T cells in blood with increased stem/memory signatures and decreased exhaustion signatures relative to their intratumoral counterparts. Number of circulating cancer-specific T cells is likely most linked to primary response to immunotherapy as longitudinal samples documented emergence of additional resistance mechanisms, amidst abundant circulating cancer-specific CD8 T cells. These results suggest that blood acts as an important reservoir of cancer-specific CD8 T cells and suggests adoptive cell therapies may be particularly effective in patients without such cells.
2023-04-01 | GSE227054 | GEO
Project description:Merkel cell carcinoma is supposed to be derived from Merkel cells after infection by Merkel cell polyomavirus (MCV) and other poorly known events. A transcriptional profiling with cDNA microarrays was performed on cells from MCV+ Merkel cell carcinomas and isolated normal Merkel cells. This microarray revealed numerous significantly upregulated genes and down-regulated genes. The extensive list of genes identified in these experiments provides a large body of potentially valuable information of Merkel cell carcinoma carcinogenesis and could represent a source of potential targets for cancer therapy. Two-conditions experiment, MCV vs Normal Merkel Cell. Biological replicates : 4 MCV (Cy5), 1 control = pool of Normal Merkel cells from 3 liftings
2014-01-01 | E-GEOD-50434 | biostudies-arrayexpress
Project description:Merkel cell carcinoma is supposed to be derived from Merkel cells after infection by Merkel cell polyomavirus (MCPyV) and other poorly known events. A transcriptional profiling with cDNA microarrays was performed on cells from MCPyV(+) Merkel cell carcinomas and isolated normal Merkel cells. This microarray revealed numerous significantly upregulated genes and downregulated genes. The extensive list of genes identified in these experiments provides a large body of potentially valuable information of Merkel cell carcinoma carcinogenesis and could represent a source of potential targets for cancer therapy.
2014-01-01 | GSE50434 | GEO
Project description:Merkel cells are epidermal mechanoreceptor cells responsible for the perception of gentle touch. Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer. Although MCC histologically resembles Merkel cells, the cell of origin for MCC is unknown. MCC frequently contains integrated Merkel cell polyomavirus (MCPyV), a small DNA tumor virus with widespread prevalence. Whether MCPyV can transform Merkel cells is unknown. Here, we describe the isolation and long-term expansion of human Merkel cells from neonatal foreskin. We validated the expression of several Merkel cell-related factors by RNASeq, and assessed the ultrastructure by electron microscopy. Culture of Merkel cell preparations on an artificial basement membrane promoted the formation of structures containing both Merkel and non-Merkel cell populations. To determine whether Merkel cells were susceptible to transformation, we expressed tumor-derived MCPyV T antigens and additional oncogenes. We were unable to demonstrate tumorigenesis in immunodeficient mice, but were able to detect T antigen expression from excised cells weeks after implantation. These results highlight that foreskin-isolated Merkel cells can be propagated extensively, sustain expression of MCPyV T antigens, but are not susceptible to transformation by MCPyV, suggesting that Merkel cells from non-glabrous skin may not be a cell of origin for MCC.
2017-04-01 | GSE79657 | GEO
Project description: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.
2025-08-01 | GSE301498 | GEO
Project description:We performed miRNA expression profiling in a series of human Merkel Cell carcinoma samples using a microarray approach. Significant differentially expressed miRNAs among groups were identified using SAM analysis. Agilent microarray platform containing 723 human miRNAs was used to determine miRNA expression profiles in 16 human Merkel cell carcinoma (MCC) samples. To validate the microarray platform, the expression levels of selected miRNAs were evaluated using qRT-PCR.
2013-12-31 | E-GEOD-43699 | biostudies-arrayexpress
Project description:Merkel cell polyomavirus (MCV) is clonally integrated in over 80% of Merkel cell carcinomas and mediates tumor development through the expression of viral oncoproteins large T (LT) and small T antigens (sT). Viral integration is associated with signature mutations in the T antigen locus that result in deletions of carboxy-terminal replicative functions of the LT antigen. Despite these truncations, the LT LxCxE retinoblastoma (Rb) pocket protein family-binding domain is retained, and the entire sT isoform is maintained intact. To investigate the ability of MCV oncoproteins to regulate host gene expression, we performed microarray analysis on cells stably expressing tumor-derived LT, tumor-derived LT along with sT, and tumor-derived LT with a mutated Rb interaction motif. Gene expression alterations in the presence of tumor-derived LT could be classified into three main groups: genes that are involved in the cell cycle (specifically the G1/S transition), genes involved in DNA replication, and genes involved in cellular movement. The LxCxE mutant LT largely reversed gene expression alterations detected with the wild type LT, while co-expression of sT did not significantly affect these patterns of gene expression. LxCxE-dependent upregulation of cyclin E and CDK2 correlates with increased proliferation in tumor-derived LT expressing cells. We conclude that in hTERT-immortalized human fibroblasts the LXCXE motif of tumor-derived LT enhances cellular proliferation and upregulates cell cycle and immune signaling gene transcription. RNA was isolated from BJ-hTERT cell lines and hybridized to an Illumina chip for global gene expression analysis
2015-09-21 | E-GEOD-68503 | biostudies-arrayexpress
Project description:Array-CGH profiles of Merkel cell carcinoma tumors Experiment Overall Design: We perfromed array-CGH on 25 Merkel cell carcinoma tumor samples (2 primary/metastasis pairs) looking for recurrent gains/losses among the cohort of tumors. Experiment Overall Design: Results from the Analysis of Copy Errors (ACE) may be found in GSE13239_MccACEAnalyzedData.txt. Experiment Overall Design: The overall profiles of the primary/metastasis pairs are similar. These metastases samples, 1m and 3m, were excluded from the ACE analysis.
2009-01-14 | E-GEOD-13239 | biostudies-arrayexpress