Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

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.

Digital Quantification of Intratumoral CD8+ T-Cells Predicts Relapse and Unfavorable Outcome in Uveal Melanoma

“…Other evidence reinforced the relationship between immune cell infiltration and prognosis, with the exception of some genetically distinct subgroups [ 28 ]. Recently, a bioinformatic analysis and CD8+ gene signature confirmed the prognostic role of CD8 in UM [ 17 , 18 ]. In addition, a recent study performing single cell analyses of the tumor and the microenvironment in primary and metastatic UMs outlined genomic complexity, as well as revealing a different subset of CD8+ T cells expressing checkpoint marker LAG3 but not PD1 or CTLA4 [ 29 ].…”

“…These studies suggested that the high immunosuppressive tumor microenvironment (TME) present in UMs caused a failure in the activation of CD8+ cells, which could not express their strong antitumoral function [ 17 ]. Unfortunately, in this context, the host’s immune system could inadvertently promote tumor growth [ 30 ].…”

“…In the context of UM, inflammatory cell infiltration has been described within and at the periphery of the tumor, especially when epithelioid cells are predominant [ 7 ]. High densities of tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) in primary UM have been correlated with a higher metastasis risk and worse prognosis [ 16 , 17 , 18 ]. Previous studies have shown that most TAMs in UMs are M2-type cells expressing CD68+ and CD163+, and survival was significantly reduced among patients with a high M2 macrophage and T cell density [ 19 , 20 , 21 , 22 ].…”

SmulTCan: A Shiny application for multivariable survival analysis of TCGA data with gene sets

“…In general, the lasso method is stricter than ridge regression due to its diamond-shaped constraint region instead of the elliptical constraint region of ridge regression, which does not set the coefficients to zero [40]. An alternative for ridge regression in the app involves the BeSS algorithm that has been recently used in the literature [41]. The "CPH" main tab in the app extracts the best subsets of input genes directly from the CPH model, and the results can be compared with those from the "glmnet" and "BeSS" tabs.…”

Uveal Melanoma Metastasis

“…However, a high metastatic infiltration of CD8+ T cells and macrophages (CD68+) correlated with longer overall survival for patients undergoing isolated hepatic perfusion as treatment of liver metastases [ 109 , 110 ]. Yet most transcriptomic and bioinformatic approaches have shown a correlation between TILs and short survival [ 111 ]. A different scenario appeared when studying the functional properties of T-cells and macrophages in depth and measuring tumor-immune cell distances in liver and extra liver metastases.…”