Dataset Information

The immune cell landscape of metastatic uveal melanoma correlates with overall survival.

ABSTRACT:

Background

Uveal 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.

Methods

We 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.

Results

Compared 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.

Conclusion

The 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.

SUBMITTER: Tosi A

PROVIDER: S-EPMC8097926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNumerous studies indicated that tumor-infiltrated immune cells (TIC) in the microenvironment are substantially linked to immunotherapy response and cancer prognosis. However, systematic studies of infiltrated immune cell characterization in uveal melanoma (UM) for prognosis and immune checkpoint blockade therapy are lacking.MethodsUM datasets were extracted from open access resources (TCGA and GEO databases). The tumor-infiltrated immune cells in the microenvironment were decoded by using the CIBERSORT algorithm, which was further applied to classify UM patients into subgroups using an unsupervised clustering method. The Boruta algorithm and principal component analysis were used to calculate the TIC scores for UM patients. Kaplan-Meier curves were plotted to prove the prognostic value of TIC scores. Besides, the correlations of the TIC score with clinical features, mutated characteristics, and the immune therapeutic response were subsequently investigated.ResultsAs a result, we defined three subtypes among 171 UM patients according to the TIC profiles and then calculated the TIC score to characterize the immune patterns for all patients. We discovered that high-TIC score patients with low BAP1 and high EIF1AX mutations have a better prognosis than low-TIC score patients. Activation of immune inflammatory response and increase in immune checkpoint-related genes in high-TIC score patients may account for good prognosis and immunotherapy response. Three melanoma cohorts received immunotherapy, proving that high-TIC score patients have substantial clinical and immune therapeutic improvements. Besides, several potential therapeutic agents were identified in the low-TIC score group.ConclusionOur study afforded a comprehensive view of infiltrated immune cell characterization to elucidate different immune patterns of UM. We also established a robust TIC-score signature, which may work as a prognostic biomarker and immune therapeutic predictor.

Project description:ObjectivesUveal melanoma (UM) is the most common primary intraocular malignancy in adults, and immune infiltration plays a crucial role in the prognosis of UM. This study aimed to generate an immunological marker-based predictive signature for the overall survival (OS) of UM patients.MethodsSingle-sample gene-set enrichment analysis (ssGSEA) was used to profile immune cell infiltration in 79 patients with UM from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate least absolute shrinkage and selection operator (LASSO) Cox regressions were used to determine the prognostic factors for UM and construct the predictive immunosignature. Receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves were performed to evaluate the clinical ability and accuracy of the model. In addition, the predictive accuracy was compared between the immunosignature and the Tumor, Node, Metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC). We further analyzed the differences in clinical characteristics, immune infiltrates, immune checkpoints, and therapy sensitivity between high- and low-risk groups characterized by the prognostic model.ResultsHigher levels of immune cell infiltration in UM were related to a lower survival rate. Matrix metallopeptidase 12 (MMP12), TCDD inducible poly (ADP-ribose) polymerase (TIPARP), and leucine rich repeat neuronal 3 (LRRN3) were identified as prognostic signatures, and an immunological marker-based prognostic signature was constructed with good clinical ability and accuracy. The immunosignature was developed with a concordance index (C-index) of 0.881, which is significantly better than that of the TNM staging system (p < 0.001). We further identified 1,762 genes with upregulated expression and 798 genes with downregulated expression in the high-risk group, and the differences between the high- and low-risk groups were mainly in immune-related processes. In addition, the expression of most of the immune checkpoint-relevant and immune activity-relevant genes was significantly higher in the high-risk group, which was more sensitive to therapy.ConclusionWe developed a novel immunosignature constructed by MMP12, TIPARP, and LRRN3 that could effectively predict the OS of UM.