Recent Advances and Challenges in Uveal Melanoma Immunotherapy

Fu, Yihang; Xiao, Wei; Mao, Yuxiang

doi:10.3390/cancers14133094

Cited by 26 publications

(20 citation statements)

References 184 publications

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“…Focal radiation therapy, including proton-beam radiation therapy, is a commonly used treatment modality to rescue the eye and can achieve high tumor control rates in over 90% of patients ( 2 ). Whereas primary UM can get local control, 50% of UM will eventually metastasize ( 6 ). Both uveal melanoma and cutaneous melanoma originate from melanocytes, but there are significant differences in their pathological features and treatment outcomes ( 1 , 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…The eye is an immune-privileged organ giving a growth advantage to primary UM, and immune privilege may be responsible for immune evasion and systemic metastasis ( 2 , 6 ). Given the immunosuppressive microenvironment of UM ( 6 ), it is important to understand the link between risk scores and immunological characteristics of UM samples. Our study identified a clear difference in immune cell infiltration among high- and low-risk groups.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study showed that the 5-year and 15-year disease-related mortality rates for uveal melanoma patients were 31% and 40%, respectively ( 5 ). In addition, approximately half of the patients develop metastases, resulting in a poor prognosis, regardless of treatment for the primary tumor ( 1 , 5 , 6 ). Metastatic UM exhibits a poor response to chemotherapy or targeted therapy, and median survival in metastatic UM is about one year ( 1 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

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Development and validation of immunogenic cell death-related signature for predicting the prognosis and immune landscape of uveal melanoma

Cai

et al. 2022

Front. Immunol.

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IntroductionUveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, and the main treatment for UM is currently surgery and plaque brachytherapy. UM is highly susceptible to metastasis, which eventually occurs in nearly half of all patients; once metastasis occurs, patients have a poor prognosis and the condition is difficult to treat. Therefore, the identification of new and effective UM biomarkers is vital for the application of therapeutic strategies. Immunogenic cell death (ICD) is a type of regulatory cell death that activates adaptive immune responses and generates long-term immunological memory. ICD can promote antitumor immunity, which may be a potential immunotherapeutic strategy for UM.MethodsThe data of UM from the Cancer Genome Atlas (TCGA) was used as a training set and the data from Gene Expression Omnibus (GEO) was used as a validation set. To determine the expression pattern of ICD-related genes in UM, survival analysis and difference analysis was conducted. The ICD-related risk signature was constructed by employing the least absolute shrinkage and selection operator (LASSO) Cox regression. Subsequently, immune profile and somatic mutation analysis were performed. In addition, cell experiments were performed to verify the role of immunogenic cell death-related genes in UM.ResultsIn this study, we analyzed the relationship between ICD-related gene expression and UM patient prognosis, somatic mutations, and the tumor immune microenvironment. Importantly, we constructed a 5-gene ICD-related risk signature and confirmed it as a novel prognostic biomarker in UM patients. We found that the high-risk group had more immune cell infiltration and a worse prognosis than the low-risk group. In cellular experiments, we confirmed the high expression of FOXP3 inMUM2B andOCM-1A cell lines and that knockdown of FOXP3 markedly inhibited the proliferation of UM tumor cells.DiscussionICD-related genes play a critical role in the tumor immune microenvironment. Our results may contribute to the development of effective immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development and validation of immunogenic cell death-related signature for predicting the prognosis and immune landscape of uveal melanoma

Cai

et al. 2022

Front. Immunol.

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“…Specific aspects of choroidal microenvironment participate in the physiological mechanisms that the eye uses to give tumor metastases a growth advantage as an immunologically privileged organ [ 27 ]. A recent study showed that this immune-privileged microenvironment limited the effectiveness of immunotherapy in an intraocular metastasis mouse model.…”

Section: Treatment Optionsmentioning

confidence: 99%

How to Manage a Patient with Ocular Metastases?

et al. 2022

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Ocular metastases are the most frequent ocular malignant tumors; their prevalence is estimated around 5–10% and is even higher in patients with breast or lung cancer. They represent various clinical situations, but they share the same hierarchical multidisciplinary therapeutic challenge with respect to the way systemic and local therapies should be selected in combination or sequentially in the personalized medical history of a patient. The challenges include tumor control, eye preservation, and the minimization of iatrogenic damage to sensitive tissues surrounding the tumor in order to preserve vision. These aims should further contribute to maintaining quality of life in patients with metastases. Many patients with choroidal metastases have systemic molecular treatment for their primary tumor. However, secondary resistance to systemic treatment is common and may ultimately be associated with cancer relapse, even after an initial response. Therefore, it makes sense to propose local treatment concomitantly or after systemic therapy to provide a more sustainable response. The aim of this review is to present current therapeutic strategies in ocular metastases and discuss how to tailor the treatment to a specific patient.

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“…Uveal melanoma (UVM) is the most common primary intraocular malignancy in adults (85%) and is highly malignant, invasive, and extremely metastatic with a poor prognosis [ 1 , 2 ]. In current practice, the first-line treatment of primary uveal melanoma is local ocular treatment, including plaque brachytherapy, local resection, and enucleation [ 3 ]. Over the last 5 years, novel prognostic biomarkers have been identified, including histone deacetylase HDAC-2 [ 4 ], DNA damage response protein ATR [ 5 ], and genes of the NF-κB pathway [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

TAP1, a potential immune-related prognosis biomarker with functional significance in uveal melanoma

et al. 2023

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Background TAP1 is an immunomodulation-related protein that plays different roles in various malignancies. This study investigated the transcriptional expression profile of TAP1 in uveal melanoma (UVM), revealed its potential biological interaction network, and determined its prognostic value. Methods CIBERSORT and ESTIMATE bioinformatic methods were used on data sourced from The Cancer Genome Atlas database (TCGA) to determine the correlation between TAP1 expression, UVM prognosis, biological characteristics, and immune infiltration. Gene set enrichment analysis (GSEA) was used to discover the signaling pathways associated with TAP1, while STRING database and CytoHubba were used to construct protein–protein interaction (PPI) and competing endogenous RNA (ceRNA) networks, respectively. An overall survival (OS) prognostic model was constructed to test the predictive efficacy of TAP1, and its effect on the in vitro proliferation activity and metastatic potential of UVM cell line C918 cells was verified by RNA interference. Results There was a clear association between TAP1 expression and UVM patient prognosis. Upregulated TAP1 was strongly associated with a shorter survival time, higher likelihood of metastasis, and higher mortality outcomes. According to GSEA analysis, various immunity-related signaling pathways such as primary immunodeficiency were enriched in the presence of elevated TAP1 expression. A PPI network and a ceRNA network were constructed to show the interactions among mRNAs, miRNAs, and lncRNAs. Furthermore, TAP1 expression showed a significant positive correlation with immunoscore, stromal score, CD8+ T cells, and dendritic cells, whereas the correlation with B cells and neutrophils was negative. The Cox regression model and calibration plots confirmed a strong agreement between the estimated OS and actual observed patient values. In vitro silencing of TAP1 expression in C918 cells significantly inhibited cell proliferation and metastasis. Conclusions This study is the first to demonstrate that TAP1 expression is positively correlated with clinicopathological factors and poor prognosis in UVM. In vitro experiments also verified that TAP1 is associated with C918 cell proliferation, apoptosis, and metastasis. These results suggest that TAP1 may function as an oncogene, prognostic marker, and importantly, as a novel therapeutic target in patients with UVM.

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Recent Advances and Challenges in Uveal Melanoma Immunotherapy

Cited by 26 publications

References 184 publications

Development and validation of immunogenic cell death-related signature for predicting the prognosis and immune landscape of uveal melanoma

Development and validation of immunogenic cell death-related signature for predicting the prognosis and immune landscape of uveal melanoma

How to Manage a Patient with Ocular Metastases?

TAP1, a potential immune-related prognosis biomarker with functional significance in uveal melanoma

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