Abstract
Purpose :
Uveal melanoma (UM) is the most common primary eye cancer and remains uniformly fatal. In contrast to cutaneous melanoma, UM is an immunologically “cold” tumor that is poorly responsive to immunotherapy. The purpose of this study was to bioinformatically deconvolute the tumor immune microenvironment (TIM) after stratification for key molecular biomarkers associated.
Methods :
RNA-seq data were downloaded from The Cancer Genome Atlas Uveal Melanoma (TCGA-UVM) dataset (n=80). Samples were stratified by gene expression profile (GEP) class 1 versus class 2, PRAME expression (negative versus positive), and LAG3 expression (low versus high). TIM deconvolution was performed using Quantiseq from the Immunedeconv R package.
Results :
Class 2 UM were inferred to comprise 2.64-fold fewer CD4+ T cells (p =0.0013), 2.3-fold fewer myeloid dendritic cells (p=0.026), 1.74-fold more M2 macrophages (p=4.37E-9), 2.02-fold more NK cells (p=1.2E-6), and 53-fold more CD8+ T cells (p=0.0007) compared to class 1 UM. PRAME-positive UM contained 1.26-fold more M2 macrophages (p=0.022), 1.39-fold more NK cells (p=0.005), and 2.29-fold fewer CD4+ T cells (p=0.0054) than PRAME-negative UM. LAG3 expression was strongly associated with class 2 UM (p=0.0026), increased M1 (p=0.00057) and M2 macrophages (p=5.6E-6), NK cells (p= 0.016), CD8+ T cells (p=1.77E-11), Tregs (p=2.27E-5), and decreased CD4+ T cells (p=0.0045).
Conclusions :
The two strongest predictors of metastasis in UM – class 2 GEP and PRAME expression – are strongly associated with an inhibitory TIM. LAG3, which we recently showed by single cell RNA sequencing to be the predominant T cell exhaustion marker in UM, was associated with an increased global inflammatory signature. The data suggest that a subset of Class 2 Tumors are prime candidates for LAG3 Immune Checkpoint Inhibition. Correlation between key molecular biomarkers and TIM will facilitate the development of targeted immune therapy for patients with UM.
This is a 2021 ARVO Annual Meeting abstract.