Dataset Information

MicroRNA-155 coordinates the immunological landscape within murine melanoma and correlates with immunity in human cancers.

ABSTRACT: miR-155 has recently emerged as an important promoter of antitumor immunity through its functions in T lymphocytes. However, the impact of T cell-expressed miR-155 on immune cell dynamics in solid tumors remains unclear. In the present study, we used single-cell RNA sequencing to define the CD45+ immune cell populations at different time points within B16F10 murine melanoma tumors growing in either wild-type or miR-155 T cell conditional knockout (TCKO) mice. miR-155 was required for optimal T cell activation and reinforced the T cell response at the expense of infiltrating myeloid cells. Further, myeloid cells from tumors growing in TCKO mice were defined by an increase in wound healing genes and a decreased IFN-?-response gene signature. Finally, we found that miR-155 expression predicted a favorable outcome in human melanoma patients and was associated with a strong immune signature. Moreover, gene expression analysis of The Cancer Genome Atlas (TCGA) data revealed that miR-155 expression also correlates with an immune-enriched subtype in 29 other human solid tumors. Together, our study provides an unprecedented analysis of the cell types and gene expression signatures of immune cells within experimental melanoma tumors and elucidates the role of miR-155 in coordinating antitumor immune responses in mammalian tumors.

SUBMITTER: Ekiz HA

PROVIDER: S-EPMC6482995 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MicroRNA-155 coordinates the immunological landscape within murine melanoma and correlates with immunity in human cancers.

Ekiz H Atakan HA Huffaker Thomas B TB Grossmann Allie H AH Stephens W Zac WZ Williams Matthew A MA Round June L JL O'Connell Ryan M RM

JCI insight 20190321 6

miR-155 has recently emerged as an important promoter of antitumor immunity through its functions in T lymphocytes. However, the impact of T cell-expressed miR-155 on immune cell dynamics in solid tumors remains unclear. In the present study, we used single-cell RNA sequencing to define the CD45+ immune cell populations at different time points within B16F10 murine melanoma tumors growing in either wild-type or miR-155 T cell conditional knockout (TCKO) mice. miR-155 was required for optimal T c ...[more]

PMID: 30721153

Similar Datasets

Project description:Cutaneous melanoma is a severe and life-threatening form of skin cancer with growing incidences. While novel interventions have improved prognoses for these patients, early diagnosis of targeted treatment remains the most effective approach. MicroRNAs have grown to good use as potential biomarkers for early detection and as targets for treatment. miR-155 is well-studied for its role in tumor cell survival and proliferation in various tissues, although its role in melanoma remains controversial. In silico data analysis was performed in the dbDEMC v.3 to identify differentially expressed miRNA. We validated gene targets in melanoma using TarBase v8.0 and miRPath v3.0 and determined protein-protein interactions of the target genes. One hundred forty patients (age range 21-90 years) with cutaneous melanoma who underwent resection were included. Molecular assessment using Real-Time RT-qPCR, clinicopathological associations, and a literature review for the different roles of miR-155 in melanoma were performed. Analysis of the dbDEMC reveals controversial findings. While there is evidence of upregulation of miR-155 in primary and metastatic melanoma samples, others suggest decreased expression in later-stage melanoma and cases with brain metastasis. miR-155 has been overexpressed in prior cases of melanoma and precancerous lesions, and it was found to be dysregulated when compared to benign nevi. While miR-155 expression was associated with favorable outcomes in some studies, others showed an association with metastasis. Patients with high levels of miR-155 also noted reduction after receiving anti-PD-1 treatment, correlated with more prolonged overall survival. In our patient's cohort, 22.9% relapsed during treatment, and 45% developed recurrence, associated with factors such as lymph node infiltration, high mitotic index, and positive staining for CD117. Although overall analysis revealed miR-155 downregulation in melanoma specimens compared to non-cancer tissues, increased expression of miR-155 was associated with cases of superficial spreading melanoma subtype (p = 0.005) and any melanoma with a high mitotic rate (p = 0.010). The analysis did not identify optimum cutoff values to predict relapse, recurrence, or mortality. In conclusion, miR-155 could have, in part, a potential prognostic utility in cutaneous melanoma. Further mechanistic studies are required to unravel the multifunctional role of miR-155 in melanoma.

Project description:BackgroundUveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis.MethodsWe collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival.ResultsCompared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy.ConclusionThe results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis.

Dataset Information

MicroRNA-155 coordinates the immunological landscape within murine melanoma and correlates with immunity in human cancers.

Publications

MicroRNA-155 coordinates the immunological landscape within murine melanoma and correlates with immunity in human cancers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets