Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Krishna, Yamini; Acha-Sagredo, Amelia; Sabat-Pośpiech, Dorota; Kipling, Natalie; Clarke, Kim; Figueiredo, Carlos R.; Kalirai, Helen; Coupland, Sarah E.

doi:10.3390/cancers12102832

Cited by 33 publications

(40 citation statements)

References 114 publications

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“…They performed NanoStringbased transcriptomic profiling of 40 mUM liver samples in comparison with 6 control liver specimens. They confirmed their preliminary data (Krishna et al, 2017;Figueiredo et al, 2020) by demonstrating that the M2 macrophage actively contributed to the immunosuppressive environment within the mUM and was characterized by the upregulation of AXNA1, CD74, CXCR4, MIF, STAT3, PLA2G6, and TGFB1 in addition to previously described genes, such as LGALS3 and HLA-DRA (Krishna et al, 2020). This study also revealed several novel genes that were upregulated by mUM, such as DUSP4, IRF4/MUM1, and CD44 (Krishna et al, 2020).…”

Section: Current Trends In Single-cell Technology For Uveal Melanomasupporting

confidence: 83%

“…Although attempts have been made to improve our molecular understanding of the tumor microenvironment of UM by the microdissection of these subpopulations of cells and the application of NGS, these studies are still limited to the use of the bulk cells approach (Karlsson et al, 2020 ; Krishna et al, 2020 ).…”

Section: Current Trends In Single-cell Technology For Uveal Melanomamentioning

confidence: 99%

“…Krishna et al ( 2020 ) also focused on interrogating the TME in mUM liver deposits. They performed NanoString-based transcriptomic profiling of 40 mUM liver samples in comparison with 6 control liver specimens.…”

Section: Current Trends In Single-cell Technology For Uveal Melanomamentioning

confidence: 99%

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Applying Single-Cell Technology in Uveal Melanomas: Current Trends and Perspectives for Improving Uveal Melanoma Metastasis Surveillance and Tumor Profiling

Wang

Chen

Lynn

et al. 2021

Front. Mol. Biosci.

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Uveal melanoma (UM) is the most common primary adult intraocular malignancy. This rare but devastating cancer causes vision loss and confers a poor survival rate due to distant metastases. Identifying clinical and molecular features that portend a metastatic risk is an important part of UM workup and prognostication. Current UM prognostication tools are based on determining the tumor size, gene expression profile, and chromosomal rearrangements. Although we can predict the risk of metastasis fairly accurately, we cannot obtain preclinical evidence of metastasis or identify biomarkers that might form the basis of targeted therapy. These gaps in UM research might be addressed by single-cell research. Indeed, single-cell technologies are being increasingly used to identify circulating tumor cells and profile transcriptomic signatures in single, drug-resistant tumor cells. Such advances have led to the identification of suitable biomarkers for targeted treatment. Here, we review the approaches used in cutaneous melanomas and other cancers to isolate single cells and profile them at the transcriptomic and/or genomic level. We discuss how these approaches might enhance our current approach to UM management and review the emerging data from single-cell analyses in UM.

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Section: Current Trends In Single-cell Technology For Uveal Melanomasupporting

confidence: 83%

Section: Current Trends In Single-cell Technology For Uveal Melanomamentioning

confidence: 99%

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Applying Single-Cell Technology in Uveal Melanomas: Current Trends and Perspectives for Improving Uveal Melanoma Metastasis Surveillance and Tumor Profiling

Wang

Chen

Lynn

et al. 2021

Front. Mol. Biosci.

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“…BAFF was able to promote the activities of B cells, CD4 + and CD8 + T cells [ 27 , 28 ]. Prior reports indicated that the tumor-infiltrating immune cells played a key role in the metastatic process of UM [ 18 , 29 , 30 , 31 , 32 ]. Besides the immune-associated mechanism, the BAFF gene was also reported to participate in the progression of malignancies through interacting with pluripotency-associated genes and epithelial mesenchymal transition (EMT)-associated genes [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a Three-Marker Panel for the Detection of Uveal Melanoma Metastases: A Single-Center Retrospective Analysis

Lin

Süßkind

2021

Cancers

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Blood-based B-cell activating factor (BAFF), growth differentiation factor-15 (GDF-15) and osteopontin (OPN) have been identified to be promising biomarkers for the metastases of uveal melanoma (UM). This study intended to assess their kinetics and to evaluate their significance as a three-marker panel. A group of 36 UM patients with and 137 patients without metastases were included in the study. Their plasma OPN levels were measured by ELISA; serum BAFF and GDF-15 levels were determined with a Luminex MAGPIX system. Receiver operating characteristic (ROC) analysis was performed to calculate the cutoff values of the three markers for identifying the patients with metastases. The ability to identify patients with metastases was compared between the single markers and the combination as a three-marker panel. By using the Student’s t-test, we also investigated the kinetic changes of the levels of BAFF, GDF-15 and OPN across six periods (i.e., 0–6 months, 6–12 months, 12–18 months, 18–24 months, >24 months and post-metastasis) before the imaging diagnosis of metastases. By maximizing the Youden’s index, the serum GDF-15 level of 1209 pg/mL and the plasma OPN level of 92 ng/mL were identified to have the best performance for distinguishing the metastatic patients from non-metastatic patients. The three-marker panel offered a better performance in distinguishing patients with metastases, with an area under the curve of 0.802, than any single biomarker. Increasing trends of the levels of three biomarkers were observed in the two-year period before the imaging diagnosis of metastases. The combined panel of BAFF, GDF-15 and OPN might be a utilizable implementation for the detection of UM metastases. In the bioinformatics study with two external datasets, the high expression of gene BAFF and GDF-15 in primary UM tissues was identified to be associated with poor overall survival rates. As the current work is a single-center retrospective study, more well-designed prospective investigations employing larger cohorts are urgently needed to validate our findings.

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“…The presence of TILs is a marker of good prognosis for many cancers but not in UM where it is associated with a poor prognosis [ 57 , 58 ]. Why this is so is not fully understood, as there are contradictory reports on the immune cell subtypes populating liver metastases in UM [ 59 , 60 , 61 , 62 , 63 ]. It is of note that most studies that tried to characterize the immunosuppressive environment in UM metastases have been performed at the transcriptomic level on only very few immune cells.…”

Section: Immunobiology Of Uveal Melanomamentioning

confidence: 99%

How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma

Marseglia

Amaro

Solari

et al. 2021

Cancers

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Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP-kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunitsGNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP–TAZ pathway that is also activated in UM, the tumor-suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti-PD-1 and anti-CTLA-4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross-talk between tumor and immune cells could help to reshape anti-tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.

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Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Cited by 33 publications

References 114 publications

Applying Single-Cell Technology in Uveal Melanomas: Current Trends and Perspectives for Improving Uveal Melanoma Metastasis Surveillance and Tumor Profiling

Applying Single-Cell Technology in Uveal Melanomas: Current Trends and Perspectives for Improving Uveal Melanoma Metastasis Surveillance and Tumor Profiling

Evaluation of a Three-Marker Panel for the Detection of Uveal Melanoma Metastases: A Single-Center Retrospective Analysis

How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma

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