Abstract
Tumor-infiltrating immune cells are capable of effective cancer surveillance, and their abundance is linked to better prognosis in numerous tumor types. However, in uveal melanoma (UM), extensive immune infiltrate is associated with poor survival. This study aims to decipher the role of different tumor-infiltrating cell subsets in UM in order to identify potential targets for future immunotherapeutic treatment. We have chosen the TCGA-UVM cohort as a training dataset and GSE22138 as a testing dataset by mining publicly available databases. The abundance of 22 immune cell types was estimated using CIBERSORTx. Then, to determine the significance of tumor-infiltrating cell subsets in UM, we built a multicell type prognostic signature, which was validated in the testing cohort. The created signature was built upon the negative prognostic role of CD8+ T cells and M0 macrophages and the positive role of neutrophils. Based on the created signature score, we divided the patients into low- and high-risk groups. Kaplan-Meier, Cox, and ROC analyses demonstrated superior performance of our risk score compared to either clinical or pathologic characteristics of both cohorts. Further, we found the molecular pathways associated with cancer immunoevasion and metastasis to be enriched in the high-risk group, explaining both the lack of adequate immune surveillance despite increased infiltration of CD8+ T cells as well as the higher metastatic potential. Genes associated with tryptophan metabolism (IDO1 and KYNU) and metalloproteinases were among the most differentially expressed between the high- and low-risk groups. Our correlation analyses interpreted in context of published in vitro data strongly suggest the central role of CD8+ T cells in shifting the UM tumor microenvironment towards suppressive and metastasis-promoting. Therefore, we propose further investigations of IDO1 and metalloproteinases as novel targets for immunotherapy in lymphocyte-rich metastatic UM patients.
Highlights
Uveal melanoma (UM) is the most common primary eye cancer in adults and the second most common type of melanoma
After filtering by censor time and CIBERSORTx deconvolution’s p value, 71 cases from the TCGA-UVM dataset were used as a training dataset, 60 from GSE22138 as a testing dataset, and 442 patients from the cutaneous melanoma (CM) TCGA-SKCM dataset were used as a comparison to TCGA-UVM
To enumerate the tumor-infiltrating immune cells, we utilized the CIBERSORTx algorithm, which through ν-support vector regression (ν-SVR) can accurately estimate cell abundance based on the supplied gene expression profile [40]
Summary
Uveal melanoma (UM) is the most common primary eye cancer in adults and the second most common type of melanoma. In the course of cancer microevolution, neoplastic cells undergo a series of adjustments adapting the cells to increased proliferation and selective pressure from the immune system [11, 12] These changes induce the formation of a hostile tumor microenvironment (TME) capable of inhibiting the immune cell effector function [11,12,13]. Novel strategies emerging in cancer research are aimed at targeting the TME in order to restore proper immunosurveillance. Checkpoint inhibition representing such an approach has been proven effective in the treatment of several cancers, achieving spectacular success in the therapy of cutaneous melanoma (CM) [17]
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