Abstract
BackgroundCD8+ T cells work as a key effector of adaptive immunity and are closely associated with immune response for killing tumor cells. It is crucial to understand the role of tumor-infiltrating CD8+ T cells in uveal melanoma (UM) to predict the prognosis and response to immunotherapy.Materials and MethodsSingle-cell transcriptomes of UM with immune-related genes were combined to screen the CD8+ T-cell-associated immune-related genes (CDIRGs) for subsequent analysis. Next, a prognostic gene signature referred to tumor-infiltrating CD8+ T cells was constructed and validated in several UM bulk RNA sequencing datasets. The risk score of UM patients was calculated and classified into high- or low-risk subgroup. The prognostic value of risk score was estimated by using multivariate Cox analysis and Kaplan–Meier survival analysis. Moreover, the potential ability of gene signature for predicting immunotherapy response was further explored.ResultsIn total, 202 CDIRGs were screened out from the single-cell RNA sequencing of GSE139829. Next, a gene signature containing three CDIRGs (IFNGR1, ANXA6, and TANK) was identified, which was considered as an independent prognostic indicator to robustly predict overall survival (OS) and metastasis-free survival (MFS) of UM. In addition, the UM patients were classified into high- and low-risk subgroups with different clinical characteristics, distinct CD8+ T-cell immune infiltration, and immunotherapy response. Gene set enrichment analysis (GSEA) showed that immune pathways such as allograft rejection, inflammatory response, interferon alpha and gamma response, and antigen processing and presentation were all positively activated in low-risk phenotype.ConclusionOur work gives an inspiration to explain the limited response for the current immune checkpoint inhibitors to UM. Besides, we constructed a novel gene signature to predict prognosis and immunotherapy responses, which may be regarded as a promising therapeutic target.
Highlights
Uveal melanoma (UM) is the most common intraocular malignant tumor in adult, but much rarer than skin cutaneous melanoma (CM)
We astonishingly found that infiltration of CD8+ T cells will risk UM patients (Figure 1A tumor-infiltrating CD8+ T cells work as a protective factor for and Supplementary Table 2)
Know, successful application of immune checkpoint blockade in CM greatly depends on the ability of anti-tumor immune response, which largely owes to the density of tumor-infiltrating CD8+ T cells (Tavera et al, 2018)
Summary
Uveal melanoma (UM) is the most common intraocular malignant tumor in adult, but much rarer than skin cutaneous melanoma (CM). The incidence of UM is one thousandth of 0.06–0.07, and around 50% of UM patients will eventually die from metastases (Singh et al, 2011; Goh et al, 2020). Despite both UM and CM originate from similar cell types, cancer cells in UM are biologically different from CM (Heppt et al, 2017b). CD8+ T cells work as a key effector of adaptive immunity and are closely associated with immune response for killing tumor cells. It is crucial to understand the role of tumor-infiltrating CD8+ T cells in uveal melanoma (UM) to predict the prognosis and response to immunotherapy
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